JP2009545531A - Phosphonate vinyl lysophosphatidic acid receptor antagonist - Google Patents

Abstract

The present invention provides LPA analogs that are antagonists at the LPA receptor.

Description

  No description

Lysophosphatidic acid (LPA) is a lysophospholipid mediator that can induce diverse responses when applied to living mammalian cells. This includes calcium mobilization, cytoskeletal changes that can lead to increased migration, increased cell survival, resistance to apoptosis and mitogenesis. LPA is also believed to promote platelet aggregation in many mammalian species, including humans. Furthermore, LPA is a pro-angiogenic factor. LPA signals through a suite of at least three G protein-coupled receptors named LPA ₁ , LPA ₂ and LPA ₃ (formerly EDG2, EDG4 and EDG7). Other receptors for LPA have been suggested, including the G protein-coupled receptors GPR23 and GPR92 and the nuclear hormone receptor (PPAR-γ).

  LPA is one of the intermediates present during phospholipid biosynthesis in every cell. This is generated through a common novel phospholipid biosynthetic pathway. Extracellular (plasma) LPA is primarily derived from the action of plasma phosphodiesterase, an autotaxin (ENPP-2), on lysophosphatidylcholine (LPC). LPA levels in human plasma have been reported to be in the range of about 200-600 nanomolar (nM). LPA in serum is obtained from directly and indirectly activated platelets. Serum LPA concentrations are in the range of about 2-6 micromolar (μM). Extracellular LPA accumulation is a characteristic of ascites that can often accompany human ovarian cancer. LPA is thought to be a mitogenic stimulator of ovarian cancer cells. LPA concentrations in these malignant ascites have been reported to be in the range of about 2-50 μM.

It has been suggested that LPA has a role in preventing the progression of neoplastic diseases. However, this was difficult to prove due to the lack of suitable LPA receptor antagonist molecules. LPA is angiogenic in the chick embryo chorioallantoic membrane model, suggesting a role for LPA signaling in angiogenic processes such as tumor growth. In mice lacking the LPA ₁ receptor gene, neuropathic pain usually does not occur, suggesting a role for this receptor type in the development of neuropathic pain.

  There is currently a need for new powerful and selective compounds and methods for preventing cancer progression. There is a long-standing need to identify LPA receptor antagonists that can modulate the activity of one or more LPA receptors. The present invention satisfies these needs.

  In one aspect, the present invention provides compounds having antagonist activity at one or more LPA receptors. The compound is an LPA analog that can act as an antagonist at the LPA receptor. Accordingly, the following compounds of formula I are provided:

I
In this formula, Z is —CY═CH— or —C≡C—, wherein when Z is —CY═CH—, the double bond has a trans (e) structure, Y is hydrogen or halogen, Each R ¹ is independently halo, (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -NH ₂ , -NH (C ₁ -C ₆ ) Alkyl, -N ((C ₁ -C ₆ ) alkyl) ₂ , or cyano, and R ² is hydrogen, halo, (C ₁ -C ₁₂ ) alkyl, halo (C ₁ -C ₁₂ ) alkyl, halo (C ₁ -C ₁₂ ) alkoxyl, (C ₃ -C ₁₂ ) cycloalkyl, (C ₂ -C ₁₂ ) alkenyl, (C ₂ -C ₁₂ ) alkynyl, -NH ₂ , -NH (C ₁ -C ₁₂ ) Alkyl, -N ((C ₁ -C ₁₂ ) alkyl) ₂ , (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₁₂ ) alkaryl, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₁₂ ) alkyl Or (C ₆ -C ₁₀ ) aryl-substituted (C ₆ -C ₁₀ ) aryl (C ₁ -C ₁₂ ) alkyl. Each R ³ is independently halo, (C ₁ -C ₁₂ ) alkyl, halo (C ₁ -C ₁₂ ) alkyl, halo (C ₁ -C ₁₂ ) alkoxyl, (C ₃ -C ₁₂ ) cyclo-alkyl, (C ₂ -C ₁₂₎ alkenyl, (C ₂ -C _{12) alkynyl, -NH 2, -NH (C 1} -C 12) _{alkyl, -N ((C 1 -C 12} ) alkyl) _2, (C ₆ -C ₁₀₎ aryl, (C ₁ -C ₁₂₎ alkyl (C ₆ -C ₁₀₎ aryl, (C ₆ -C ₁₀₎ aryl (C ₁ -C ₁₂₎ alkyl or aryl substituted aryl (C ₁ -C _12, ) Alkyl. R ⁴ is (C ₆ -C ₂₄ ) alkyl, halo (C ₆ -C ₂₄ ) alkyl, (C ₆ -C ₂₄ ) alkoxy, -NH ₂ , -NH (C ₁ -C ₂₄ ) alkyl, -N ( (C ₁ -C ₂₄ ) alkyl) ₂ , cyano, (C ₃ -C ₁₀ ) -cycloalkyl, (C ₄ -C ₁₅ ) -bicycloalkyl, (C ₆ -C ₂₄ ) alkenyl, (C ₆ -C ₂₄ ) -Alkynyl, (C ₆ -C ₁₀ ) aryl, (C ₁₂ -C ₃₄ ) alkyl (C ₆ -C ₁₀ ) aryl, (C ₆ -C ₁₀ ) aryl (C ₁₂ -C ₃₄ ) alkyl, or (C _6- C ₁₀ ) aryl-substituted (C ₆ -C ₁₀ ) aryl (C ₁₂ -C ₃₄ ) alkyl, wherein the alkyl, alkenyl aryl group of R ⁴ can be optionally substituted with halo, alkoxy or cyano. R ⁵ and R ⁶ are independently hydroxy, (C ₁ -C ₁₂ ) alkyl-O-, C ₂ -C ₁₂ ) alkenyl-O-, (C ₂ -C ₁₂ ) alkynyl-O-, (C ₆ -C ₁₀₎ aryl -O-.

m is 0, 1, 2, 3, or 4 and n is 0, 1, 2, or 3, or a pharmaceutically acceptable salt or ester thereof.

  The present invention also provides esters of any compound having formula I with an ester functionality added to form a prodrug to increase oral availability.

  The present invention also provides a compound of formula (I) for use in drug therapy.

In another aspect, the present invention provides the following.
A method for inhibiting angiogenesis in a tumor, comprising contacting cancer cells with an effective amount of a compound of formula I, a pharmaceutically acceptable salt or ester thereof.
A method for preventing, preventing or treating neuropathic pain, which requires an effective amount of at least one compound of formula I or a compound of formula I and a pharmaceutically acceptable carrier. Administration to a subject is included.
A method for repairing vascular injury following catheterization, comprising contacting the lumen of an affected blood vessel with an effective amount of a compound of formula I.
Or a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in drug therapy (eg, treatment of neoplastic disease, treatment of neuropathic pain or ischemia reperfusion injury).

  In another aspect, the present invention provides a method for reducing damage resulting from ischemia reperfusion injury. Examples of ischemic reperfusion injury include myocardial infarction, ischemic stroke, ischemic reperfusion injury to the kidney and the like. The method includes administering an effective amount of a compound of formula I, a pharmaceutically acceptable salt or ester thereof, to a patient in need thereof (eg, a human).

  In another aspect, the invention provides a compound of formula I, a pharmaceutically acceptable salt or ester thereof, for preparing an agent that inhibits tumor growth, metastasis or tumor angiogenesis in a mammalian species (eg, human). Provide usage.

  In another aspect, the invention relates to drug therapy (eg, treatment of neoplastic disease, inhibition of tumor growth, treatment of neuropathic pain, or treatment of vascular injury or ischemia reperfusion injury). Provided is a compound of formula I for use, a pharmaceutically acceptable salt or ester thereof.

  In another aspect, the present invention provides prodrugs of compounds of formula I. The present invention also provides pharmaceutically acceptable salts or esters of the compounds of formula I for use in drug therapy.

  In another aspect, the present invention relates to the use of a compound of formula I, a pharmaceutically acceptable salt or ester thereof for preparing a medicament for the treatment of neuropathic pain in a mammalian species (eg human). provide.

  In another aspect, the invention provides a compound of formula I, a pharmaceutically acceptable salt or ester thereof, for preparing an agent that inhibits tumor growth, metastasis or tumor angiogenesis in a mammalian species (eg, human). Provide a method for use.

  In another aspect, the present invention provides compositions and methods for the use of LPA analogs and LPA prodrugs for the treatment of neoplastic diseases. In one aspect, this treatment is achieved by the application of LPA receptor antagonists that are effective due to their anti-angiogenic nature.

In the present invention, a compound of formula I (eg, an LPA ₁ / LPA ₃ receptor antagonist) is used in vivo or in vitro using an amount of a compound of formula I effective to bind the receptor. Also included is a method of binding to a designated receptor site consisting of: Tissues with ligands bound to designated LPA receptor sites can be used to measure the selectivity of test compounds for specific receptor subtypes or to identify potential therapeutics for the treatment of disease It can be used as a tool by contacting the aforementioned drug with the aforementioned ligand-receptor complex and measuring the extent of ligand displacement and drug binding.

  In another aspect, the present invention provides novel intermediates and processes useful for the preparation of compounds of formula I disclosed herein, including general and specific intermediates and Includes the synthesis process described in this document.

  In another aspect, the present invention provides a mechanism for the synthesis of compounds having Formula I and analogs or derivatives thereof and methods of use thereof. In another aspect, the present invention provides synthesis and modification mechanisms for preparing analogs and derivatives of compounds of formula I, and compositions and methods for using the analogs and derivatives.

  The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The following description more specifically illustrates the illustrative example. A list of examples provides guidance on which examples can be used in various combinations at multiple points throughout the application. In each example, the listed list serves only as a representative group and should not be interpreted as an exclusive list.

  The details of one or more embodiments of the invention are set forth in the accompanying description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

Figure 2 illustrates the synthesis of a general LPA antagonist. Figure 2 illustrates the synthesis of a general LPA antagonist. FIG. 6 is an illustration of LPA-driven calcium mobilization in A431 cells. FIG. 6 is an illustration of LPA-driven adenylyl cyclase inhibition in C6 glioma cells. FIG. 5 illustrates LPA-driven cell migration in A2058 cells. Fig. 3 illustrates melanoma tumor growth. Fig. 3 illustrates melanoma tumor growth. Fig. 3 illustrates melanoma tumor growth. FIG. 6 illustrates the quantification of the degree of tumor angiogenesis. FIG. 3 illustrates the ability of the disclosed compounds to inhibit angiogenesis in tumors. FIG. 3 illustrates the ability of the disclosed compounds to inhibit angiogenesis in tumors. FIG. 3 illustrates the ability of the disclosed compounds to inhibit angiogenesis in tumors. FIG. 3 illustrates the ability of the disclosed compounds to inhibit angiogenesis in tumors. Illustrated for the effect of the disclosed compounds on tactile allodynia and thermal hyperalgesia in rats, where the ligature was placed in the sciatic nerve. Illustrated for the effect of the disclosed compounds on tactile allodynia and thermal hyperalgesia in rats, where the ligature was placed in the sciatic nerve. Illustrated for the effect of the disclosed compounds on tactile allodynia and thermal hyperalgesia in rats, where the ligature was placed in the sciatic nerve. Figure 3 graphically illustrates the effect of test compounds on tumor growth. Figure 3 graphically illustrates the effect of test compounds on tumor growth. Figure 3 graphically illustrates the effect of test compounds on tumor growth. Figure 3 graphically illustrates the effect of a test compound on lytic bone metastasis.

The following abbreviations are used in this document. GPCR (G protein coupled receptor), SAR (structure activity relationship), LPA (lysophosphatidic acid), LPA ₁ , LPA ₂ , LPA ₃ (LPA receptor type), EDG (endothelial cell differentiation gene), and RT- PCR (reverse transcriptase polymerase chain reaction).

  In the description and claims of this invention, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any materials and methods similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred materials and methods are described herein. Each term below has the meaning associated with it in this section. The specific and preferred values listed below for radicals, substituents, and ranges are for illustrative purposes only, and other values defined for the radicals and substituents or other values within the defined range It does not exclude values.

“One (a)”, “One (an)”, “The (the)”, “At least one (at least
The terms “one” and “one or more” are used interchangeably. Thus, for example, a composition comprised of “an” element means one element or a plurality of elements.

  The term “receptor agonist” is a compound that mimics the action of LPA at one or more of its receptors but may have different potency and potency.

  The term “receptor antagonist” 1) lacks endogenous agonist activity and 2) blocks LPA receptor agonist (eg, LPA) activation in many completely reversible and reversible ways Compound ("competitive antagonist").

  The term “affected cell” means a cell of a subject suffering from a disease or disorder, the diseased cell having a phenotype that is different from a subject not suffering from the disease or disorder.

  A cell or tissue is “affected” by a disease or disorder if the cell or tissue has a different phenotype than the same cell or tissue in a subject not afflicted with the disease or disorder.

  A disease or disorder is “reduced” when the severity of the symptoms of the disease or disorder, the frequency with which the patient experiences the symptoms, or both are reduced.

  An “analog” of a compound is a compound that is structurally similar to another but not necessarily an isomer (eg, 5-fluorouracil is an analog of thymine).

  The terms “cell”, “cell line”, and “cell culture” can be used interchangeably.

  A “control” cell, tissue, sample or subject is a cell, tissue, sample or subject of the same type as the cell, tissue, sample or subject to be tested. A control can be tested, for example, exactly or nearly simultaneously with testing a cell, tissue, sample, or subject to be tested. A control may also be tested at a time separate from, for example, testing the cell, tissue, sample, or subject to be tested, and the results of the control test may include the recorded results of the cell being tested. , Tissue, sample, or subject may be recorded so that it can be compared with the results obtained in the examination. Controls can also be obtained from a different source or similar source than the group or subject being tested, in which case the test sample is from a subject suspected of having the disease or disorder of interest for which the test is being conducted. obtain.

  A cell, tissue, sample, or subject to be “tested” is that being examined or treated.

  When present, a cell, tissue, or sample that is “pathological” refers to the disease or disorder in which the cell, tissue, or sample is located (or from which the tissue was obtained). It is shown. As an example, the presence of one or more breast cells in the lung tissue of an animal indicates that the animal is suffering from metastatic breast cancer.

  A tissue "usually contains" a cell if one or more of the cells are present in the tissue of an animal not afflicted with a disease or disorder.

  The use of the term “detection” and its grammatical variants means measuring its species without quantification, while the use of “determining” or “measuring” and its grammatical variants is It means measuring the species by quantification. The terms “detection” and “identification” are used interchangeably herein.

  A “detectable marker” or “reporter molecule” is an atom or molecule that allows specific detection of a compound with a marker in the presence of a similar compound without the marker. Detectable markers or reporter molecules include, for example, radioisotopes, antigenic determinants, enzymes, nucleic acids that can be used for hybridization, chromophores, fluorophores, chemiluminescent molecules, electrochemically detectable molecules, and variants Molecules that provide fluorescent polarization or deformed light scattering.

  A “disease” is an animal health condition in which the animal cannot maintain homeostasis and the animal's health continues to deteriorate if the disease does not recover.

  A “disorder” in an animal is a health condition in which the animal can maintain homeostasis, but the health condition of the animal is worse than it is without a disorder. Even without treatment, the disorder does not necessarily cause further deterioration of the animal's health.

  “Effective amount” means an amount sufficient to produce a selected effect. For example, an effective amount of an LPA receptor antagonist is an amount that decreases the cell signaling activity of the LPA receptor.

  A “functional” molecule is a form of a molecule that exhibits the properties with which it is characterized. As an example, a functional enzyme is an enzyme that exhibits the characteristic catalysis by which it is characterized.

  The term “inhibits” refers to the ability of the disclosed compounds to reduce or interfere with the described function. Preferably it is at least 10% inhibited, more preferably at least 25%, even more preferably at least 50%, and most preferably its function is inhibited by at least 75%.

  “Instructions” are publications, records, charts, or any other media that can be used to communicate the usefulness of the disclosed compounds to achieve reduction of the various diseases or disorders described herein. Included in kit. Optionally, or alternatively, the instructions may describe one or more methods for alleviating a disease or disorder in a mammalian cell or tissue. The instructions for use of the kit can be attached, for example, to a container containing the disclosed compound or shipped together with a container containing the identified compound. Alternatively, the instructions can be shipped separately from the container with the intent that the instructions and compounds are used in conjunction by the recipient.

  The term “parenteral” means not by the digestive tract, but by other routes such as subcutaneous, intramuscular, intrathecal, or intravenous.

  The term "purified" and similar terms refer to a form (at least 75% removed, preferably 90% removed) that is substantially free of other components normally associated with the molecule or compound in its original environment. And most preferably related to the separation of molecules or compounds with at least 95% removal). The term “purified” does not necessarily indicate that complete purity of the particular molecule has been achieved during the process. A “high purity” compound is a compound that is greater than 90% pure. A “very highly purified” compound is a compound with a purity greater than 95%.

  A “sample” preferably refers to a biological sample taken from a subject, including but not limited to normal tissue sample, affected tissue sample, biopsy (sample), blood, saliva, feces, semen, Includes tears and urine. Samples also include any other source of specimen obtained from a subject, including predetermined cells, tissues, or body fluids. Samples can also be obtained from cell or tissue culture.

  The term “standard” refers to something used for comparison. For example, the standard may be a known standard drug or compound, which is administered or added to a control sample and is used to compare results when measuring the above compounds present in a test sample. Standards can also be used to determine whether a known amount is added to a sample and is useful in determining the purification rate, recovery rate, etc. when the sample is processed or subjected to a purification or extraction procedure before measuring a given marker. Sometimes referred to as "internal standard" such as a compound.

  A “subject” of analysis, diagnosis, or treatment is an animal. Such animals include mammals, preferably humans.

  A “by therapy” treatment is a treatment given to a subject who exhibits signs of a medical condition for the purpose of reducing or eliminating those signs.

  A “therapeutically effective amount” of a compound is that amount of the compound sufficient to provide a beneficial effect (drug effect) to the subject to whom the compound is administered.

  The term “treatment” includes prevention of a particular disorder or condition, or alleviation of symptoms associated with a particular disorder or condition, or prevention or elimination of said symptoms.

  The disclosed compounds are generally named according to IUPAC or CAS nomenclature. Abbreviations well known to those skilled in the art may be used (eg, “Ph” is phenyl, “Me” is methyl, “Et” is ethyl, “h” is time, “rt” is room temperature, and “ rac "is a racemic mixture).

  Values for radicals, substituents, and ranges are for illustrative purposes only and do not exclude other values defined for the radicals and substituents or other values within the defined ranges. The disclosed compounds include compounds of formula I having any combination of values, specific values, specific values, and preferred values described herein.

The term “halogen” or “halo” includes bromo, chloro, fluoro, and iodo. The term “haloalkyl” refers to an alkyl radical having at least one halogen substituent, including, but not limited to, chloromethyl, fluoroethyl or trifluoromethyl, and the like. The term “C ₁ -C ₂₄ alkyl” means a branched or straight chain alkyl group having 1 to 9 carbons. Non-limiting examples include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, and the like. included. The term “C ₂ -C ₂₄ alkenyl” means an olefinically unsaturated branched or straight chain group having 2 to 9 carbon atoms and at least one double bond. In general, C ₂ -C ₂₄ alkenyl groups include, but are not limited to, 1-propenyl, 2-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, hexenyl, heptenyl, octenyl, and the like Things are included. The (C ₂ -C ₂₄₎ The term alkynyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl , 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl, and the like. The term “(C ₁ -C ₂₄ ) alkoxy or alkoxyl” means an alkyl group attached through an oxygen atom. Examples of (C ₁ -C ₂₄ ) alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy, and the like . The term (C ₂ -C ₂₆ ) alkoxyalkyl includes methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, and the like.

The term “C ₃ -C ₁₂ cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

  The term “optionally substituted” means 0, 1, 2, 3 or 4 substituents, wherein each substituent is independently selected. Each independently selected substituent can be the same or different from the other substituents.

The term “(C ₆ -C ₁₀ ) aryl” means a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings, including, but not limited to, phenyl, Benzyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like are included.

The term “(C ₆ -C ₁₀ ) aryl (C ₁ -C ₂₄ ) alkyl” or “aralkyl” is substituted with a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings Refers to an alkyl group and includes groups such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. Non-limiting examples of arylalkyl include benzyl, phenylethyl, naphthylmethyl, and the like.

The term “(C ₁ -C ₂₄ ) alkyl (C ₆ -C ₁₀ ) aryl” refers to any aryl group attached to the body portion through an alkyl group, and also refers to “(C ₁ -C ₂₄ ) alkyl”. The term “(C ₆ -C ₁₀ ) aryl” means an aromatic ring attached to the body portion via an alkyl group.

  The term “optionally substituted aryl” includes aryl compounds with 0, 1, 2, 3 or 4 substituents, and substituted aryl includes 1, 2, 3 or 4 substitutions. Aryl compounds with groups are included, where substituents include groups such as alkyl, halo, or amino substituents.

A “(C ₂ -C ₁₀ ) heterocyclic group” refers to an optionally substituted monocyclic or bicyclic carbocyclic ring system containing 1, 2, or 3 heteroatoms (optionally in each ring). As used herein, heteroatoms are oxygen, sulfur, and nitrogen.

The term “(C ₄ -C ₁₀ ) heteroaryl” is an optionally substituted monocyclic or bicyclic carbocyclic ring system containing 1, 2 or 3 heteroatoms (optionally in each ring) Where heteroatoms are oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl groups include furyl, thienyl, pyridyl, and the like.

  The term “bicyclic” means a bicyclic carbocycle with a stable bridge or fusion, either unsaturated or saturated. Bicyclic rings can be attached at any carbon atom, resulting in a stable structure. In general, a bicyclic system can have from about 7 to about 12 atoms in the ring system. The term includes, but is not limited to, naphthyl, dicyclohexyl, dicyclohexenyl, and the like.

The terms "phosphate analog", "phosphate ester", "phosphonate ester" and "phosphonate analog" are composed of phosphate and phosphonate analogs, where The phosphate atom is in the +5 valent oxidation state, and one or more oxygen atoms are replaced with non-oxygen moieties, such as the phosphoric acid analogs phosphorothioic acid, phosphorodithioic acid, phosphoroselenoic acid. , Phosphorodiselenoic acid, phosphoranilothioic acid, phosphoranilide acid, phosphoramidic acid, boronolinic acid, and the like, and related counterions (eg, H, NH if such counterions are present) ₄ , Na, K, and the like).

  A “derivative” of a compound means a compound produced in one or more procedures from another compound of similar structure, such as replacing hydrogen with an alkyl, acyl, or amino group.

  The term “pharmaceutically acceptable carrier” includes phosphate buffered saline, hydroxypropyl β-cyclodextrin (HO-propyl β cyclodextrin), water, emulsion (oil / water emulsion or water / Any standard pharmaceutical carrier, such as oil emulsions), and various wetting agents. The term also includes any drug that has been approved by US federal regulatory authorities or listed in the US Pharmacopeia for use in animals, including humans.

  The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the disclosed compounds and which are not biologically or otherwise undesirable. In many cases, the disclosed compounds are capable of forming acidic or basic salts due to the presence of amino or carboxyl groups or groups similar thereto.

  “Effective amount” means an amount sufficient to produce a selected effect. For example, an effective amount of an LPA receptor agonist is an amount that decreases the cell signaling activity of the LPA receptor.

  The disclosed compounds may exist in tautomeric forms and the invention includes both mixtures and individual tautomers. For example, there is the following structure.

Is understood to represent a mixture of the following structures:

and
.

  The term 16: 0, 18: 0, 18: 1, 20: 4 or 22: 6 hydrocarbon refers to a branched or straight chain alkyl or alkenyl group, where the first integer is in the group Represents the total number of carbons and the second integer represents the number of double bonds in the group.

“LPA modulators” can be used to detect detectable changes in LPA receptor activity in vivo or in vitro (eg, as described in the examples and known in the art, such as bioassays). A compound or composition capable of inducing at least a 10% increase or decrease in LPA activity when measured. “LPA receptor” means any LPA receptor subtype (eg, LPA receptors LPA ₁ , LPA ₂ , and LPA ₃ ) unless a specific subtype is indicated.

  The disclosed compounds can contain one or more asymmetric centers in the molecule. In accordance with this disclosure, any structure that does not specify a configuration is understood to include any of a variety of optical isomers, as well as racemic mixtures thereof.

  It will be appreciated by those skilled in the art that the disclosed compounds with chiral centers exist in racemic forms with optical activity and can be isolated. The disclosed compounds include any racemic, optically active, or S, R, S, S, R, R, or R, S diastereomers of compounds having the useful properties described herein, or It is understood that stereoisomeric forms, or mixtures thereof, are included. This technique involves the preparation of such optically active forms (eg, by resolution of racemates by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatography using chiral stationary phases). Methods for determining LPA agonist activity, such as by separation), as well as using standard tests described herein, or other similar tests well known in the art are well known. In addition, some compounds may exhibit polymorphism.

Neuropathic pain is characterized by its chronic nature, the absence of overt direct causes (eg, tissue damage), hyperalgesia or allodynia. Hyperalgesia is an exaggerated response to painful stimuli. Allodynia is to recognize normal stimuli as painful (examples include clothing contact, warm or cool air, etc.). Neuropathic pain can be a sequelae of nerve damage in the limbs, such as the arms or more frequently legs. Events that trigger can include trauma, such as a traffic accident or amputation (eg, phantom limb pain). Neuropathic pain may be caused by adverse effects of medications such as vincristine or paclitaxel (Taxol ^™ ), or may be caused by diabetes (type I or type II), herpes zoster, HIV-1 infection, etc. It may occur as one of the elements. In general, neuropathic pain is not responsive to nonsteroidal anti-inflammatory drugs such as opiates or aspirin.

In another aspect, the present invention provides compositions and methods for using the LPA analogs of the present invention to prevent, inhibit or treat neuropathic pain by agonizing or antagonizing LPA receptors. provide. Pain can be nociceptive or neuropathic in nature. Neuropathic pain is characterized by its chronic nature, the absence of obvious direct causes (ie, tissue damage), and allodynia. Allodynia is to recognize normal stimuli as painful (examples include clothing contact, warm or cool air, etc.). Neuropathic pain is often a sequelae of nerve damage in the limbs, such as the arms or more frequently legs. In general, neuropathic pain is not responsive to nonsteroidal anti-inflammatory drugs such as opiates or aspirin.

  In another aspect, the present invention provides compositions and methods for the use of LPA analogs and LPA prodrugs for the treatment of neoplastic diseases. In one aspect, this treatment is achieved by the application of LPA receptor antagonists that are effective due to their anti-angiogenic nature. In another aspect, treatment is achieved by administration of a sphingosine analog that inhibits multiple substrate lipid kinases.

  The present invention also includes pharmaceutical compositions comprising the compounds of the present invention. More specifically, such compounds can be formulated as pharmaceutical compositions using carriers, excipients, solubilizers and stabilizers that are acceptable as standard pharmaceuticals known to those skilled in the art. For example, as described herein, a composition of a compound of the invention, or an analog, derivative, or variant thereof, can be used to administer an appropriate compound to a subject.

  The compounds of the present invention require a therapeutically acceptable amount of a compound of formula I, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and a pharmaceutically acceptable carrier. It is useful for the treatment of illnesses or disorders, including administration to subjects.

The present invention is directed to lysophosphatidic acid (LPA) analogs that act as receptor antagonists at one or more LPA receptors, specifically LPA ₁ , LPA ₂ , and LPA ₃ receptor types. And The present invention includes both compounds with phosphate moieties and compounds with hydrolysis-resistant phosphate surrogates, such as phosphonates, α-substituted phosphonates, In particular, the α substitution here is halogen and phosphothioic acid.

  The specific and preferred values listed below for radicals, substituents, and ranges are for illustrative purposes only, and other values defined for the radicals and substituents or other values within the defined range It does not exclude values.

  An exemplary value for Z is -CY = CH-.

  Another exemplary value of Z here is -C≡C-.

  Exemplary values for Y are hydrogen, fluorine, chlorine or bromine.

  Another exemplary value for Y is hydrogen or fluorine.

  Another exemplary value for Y is hydrogen.

  Another exemplary value for Y is fluorine.

Exemplary values for R ¹ include fluorine, chlorine, bromine, trifluoro-methyl, methoxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, or alkoxy or cyano substituted (C ₁ -C ₆ ) alkyl is included.

Further exemplary values for R ¹ include fluorine, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, 1,1,1-trifluoroethoxy, methoxy, or ethoxy.

Exemplary values for R ³ include fluorine, chlorine, bromine, trifluoro-methyl, methoxy, (C ₁ -C ₆ )
Alkyl, (C ₁ -C ₆ ) haloalkyl, or (C ₁ -C ₆ ) alkyl substituted with alkoxy or cyano are included.

Further exemplary values for R ³ include fluorine, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, 1,1,1-trifluoroethoxy, methoxy, or ethoxy.

Exemplary values for R ⁴ include alkyl or alkenyl.

Exemplary values for R ² include hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, 1,1,1-trifluoroethoxy, methoxy, Ethoxy, propoxy, butoxy, and pentoxy are included.

Exemplary values for R ² include hydrogen, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, and 1,1,1-trifluoroethoxy.

Additional exemplary values for R ² include hydrogen, trifluoromethoxy, and 1,1,1-trifluoroethoxy.

Further exemplary values for R ⁴ include C ₅ H ₁₁ , C ₆ H ₁₃ , C ₇ H ₁₄ CH═CHC ₈ H ₁₇ and C ₁₅ H ₃₁ .

Further exemplary values for R ⁴ include C ₇ H ₁₄ CH═CHC ₈ H ₁₇ and C ₁₅ H ₃₁ .

Exemplary values for R ⁵ and R ⁶ include trifluoromethoxy, 1,1,1-trifluoroethoxy, methoxy, and ethoxy.

Additional exemplary values for R ⁵ and R ⁶ include hydroxy, methoxy, and ethoxy.

R ³ values include methyl, hydroxymethyl, ethyl, hydroxyethyl, propyl, hydroxypropyl, or isopropyl.

A further value for R ³ is methyl, hydroxymethyl, ethyl, or hydroxyethyl.

The value of R ⁴ includes hydroxy or phosphate (—OPO ₃ H ₂ ).

  Certain compounds of the invention have the general formula IA and are illustrated in Table 1 below.

IA

  While not wishing to be bound by any particular theory, the compounds described herein are prodrugs, such as being activated by phosphorylation of primary alcohols to form monophosphate analogs. Be expected. Furthermore, the active drug is expected to be an antagonist at the LPA type 1 receptor.

  Where the basic or acidic nature of the compound of formula I is sufficient to form a stable non-toxic acid or base salt, the preparation and administration of the compound as a pharmaceutically acceptable salt is appropriate. Conceivable. Examples of pharmaceutically acceptable salts include salts to which organic acids formed using acids that form physiologically acceptable anions are added, such as tosylate, methanesulfone, and the like. Acid salts, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Inorganic salts may also be formed, including salts such as hydrochloride, sulfate, nitrate, bicarbonate, and carbon salts.

  Pharmaceutically acceptable salts can also be obtained using standard procedures well known in the art, for example, sufficiently basic compounds such as amines to produce physiologically acceptable anions. By reacting with the appropriate acid. Carboxylates of alkali metals (such as sodium, potassium or lithium) or alkaline earth metals (such as calcium) can also be produced.

  A salt to which a pharmaceutically acceptable base is added can be prepared from an inorganic base and an organic base. Salts from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di (substituted alkyl) amines, tri (substituted alkyl) amines, alkenyl amines, dialkenyl amines, and trialkenyls. Amine, substituted alkenyl amine, di (substituted alkenyl) amine, tri (substituted alkenyl) amine, cycloalkyl amine, di (cycloalkyl) amine, tri (cycloalkyl) amine, substituted cycloalkyl amine, disubstituted cycloalkyl amine, three Substituted cycloalkyl amine, cycloalkenyl amine, di (cycloalkenyl) amine, tri (cycloalkenyl) amine, substituted cycloalkenyl amine, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amine, aryl amine, dia Primary, secondary, triarylamine, heteroarylamine, diheteroarylamine, triheteroarylamine, heterocyclic amine, diheterocyclylamine, triheterocyclylamine, mixtures of di-amine and tri-amine, etc. Salts of secondary and tertiary amines are included, wherein at least two substituents on the amine are different and are alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Aryl, heteroaryl, or heterocyclic, and the like. Also included are amines in which two or three substituents form a heterocyclic or heteroaryl group with the amino nitrogen. Non-limiting examples of amines include isopropylamine, trimethylamine, diethylamine, tri (iso-propyl) amine, tri (n-propyl) amine, ethanolamine, 2-dimethyl-aminoethanol, tromethamine, lysine, arginine, histidine. , Caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Of course, other carboxylic acid derivatives such as carboxamides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like are also useful.

  The compounds of formula I are formulated as pharmaceutical compositions and are available in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally by intravenous, intramuscular, topical or subcutaneous routes, It can be administered to a mammalian host such as a human patient.

  Thus, the compounds can be administered systemically (eg, orally) in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an anabolic edible carrier. It can be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the patient's dietary food. For therapeutic oral administration, the active compound can be combined with one or more excipients, including injectable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and more It can be used in a similar form. Such compositions and preparations should contain at least 0.1% of active compound. Composition and formulation proportions can of course vary, and can conveniently be from about 2 to about 60% by weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

  Tablets, troches, pills, capsules, and similar forms may also include the following: That is, binders such as tragacanth, acacia, corn starch or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch, potato starch, alginic acid and the like, lubricating oils such as magnesium stearate, In addition, sweeteners such as sucrose, fructose, lactose or aspartame, and flavoring agents such as peppermint, winter green oil, or cherry flavor can also be added. When the unit dosage form is a capsule, in addition to the types of materials described above, a liquid carrier such as vegetable oil or polyethylene glycol can also be included. There may be various other materials for coating or otherwise changing the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules can be coated with gelatin, wax, shellac or sugar, and the like. A syrup or elixir may contain an active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry and orange flavor, and the like. Of course, all materials used in the preparation of any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, active compounds can be incorporated into sustained-release formulations and tools.

  The active compounds can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be formulated in water and optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, triacetin, and mixtures thereof, and in oil. Under normal storage and use conditions, these preparations contain a preservative to prevent the growth of microorganisms.

  Exemplary injection or infusion pharmaceutical dosage forms have active ingredients adapted for the immediate formulation of sterile injectable or injectable solutions or dispersions, optionally encapsulated with liposomes, Sterile aqueous solutions, dispersants or sterile powders may be included. In all cases, the ultimate dosage form (dosage form) should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or medium can be a solvent or liquid dispersion medium, such as water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glyceryl esters, and Such mixtures are included. The proper fluidity can be maintained, for example, by the production of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. Prevention of the action of microorganisms can be addressed by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be desirable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of injectable compositions can be brought about by using agents that delay absorption in the composition, for example, aluminum monostearate and gelatin.

  A sterile injectable solution is prepared by sterilizing the filter after incorporating the required amount of the active compound into the appropriate solvent, if necessary, with various other ingredients listed above. . In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is by vacuum drying and freeze-drying techniques, so that in addition to the active ingredient powder, it is present in a pre-sterilized and filtered solution. Other components desired are generated.

  For topical administration, the compound can be applied in pure form, for example when it is a liquid. In general, however, they are desirably administered to the skin as a composition or formulation in combination with a dermatologically acceptable carrier, which may be solid or liquid.

  Exemplary solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, alcohols or glycols, or hydroalcohol / glycol mixtures, where the compound is dissolved or at an effective level, optionally with the aid of a non-toxic surfactant. Can be distributed. Adjuvants (adjuvants) such as fragrances and other antimicrobial agents can be added to optimize the properties for a given application. The resulting liquid composition can be applied with a water absorbent pad, soaked in a bandage or other dressing, or sprayed onto the affected area using a pump or aerosol sprayer.

  Apply thickeners, such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose and modified minerals, along with liquid carriers, to apply directly to the user's skin Pastes, gels, ointments, soaps, and the like can be formed.

  Examples of useful dermatological compositions that can be used to deliver a compound of formula I to the skin are known in the art, for example, Jacquet et al. (US Pat. No. 4,608,392), Geria (US Pat. No. No. 4,992,478), Smith et al. (US Pat. No. 4,559,157) and Wortzman (US Pat. No. 4,820,508).

  Useful dosages of the compounds of Formula I can be determined by comparing in vitro activity and in vivo activity in animal models. Methods for estimating human doses from effective doses in mice and other animals are known in the art (see, eg, US Pat. No. 4,938,949).

  Generally, the concentration of the compound of formula I in a liquid composition such as a lotion will be about 0.1 to about 25 weight percent, preferably about 0.5 to 10 weight percent. The concentration in a semi-fluid or solid composition, such as a gel or powder, will be about 0.1-5 weight percent, preferably about 0.5-2.5 weight percent, based on the total weight of the composition.

  The amount of compound or active salt or derivative required for therapeutic use will vary not only depending on the particular salt selected, but also on the route of administration, the nature of the disease being treated, and the age and condition of the patient. In the end, it is the judgment of the doctor / clinician in charge.

  In general, however, suitable doses will be in the range of about 0.5 to about 100 mg / kg, such as about 10 to about 75 mg / kg body weight per day, 3 to about 50 mg per kilogram of recipient body weight, etc. And preferably in the range of 6 to 90 mg / kg / day, most preferably in the range of 15 to 60 mg / kg / day.

  The compound is conveniently administered, for example, in unit dosage forms containing 5-1000 mg, conveniently 10-750 mg, most conveniently 50-500 mg of active ingredient per unit dosage form.

  Ideally, the active ingredient will achieve a peak plasma concentration of the active compound of about 0.5 to about 75 μM, preferably about 1 to 50 μM, and most preferably about 2 to about 30 μM. Should be administered. This can be accomplished, for example, by administering a 0.05-5% solution of the active ingredient (optionally in saline) by intravenous injection or orally as a bolus containing about 1-100 mg of the active ingredient. Preferred blood levels may be maintained by supplying about 0.01-5.0 mg / kg / hr by continuous infusion or by intermittent infusions containing about 0.4-15 mg / kg of the active ingredient.

  Preferred doses are conveniently presented in single doses or in divided doses to be administered in small doses at appropriate intervals, e.g. 2, 3, 4, or more times per day. sell. The small dose itself can be further divided, for example, into a number of distributed roughly spaced doses, such as by multiple inhalations from an inhaler or by multiple eye drops on the eye .

  Disclosed methods include kits comprising an inhibitor compound of formula I and instructions describing administration of the inhibitor compound or a composition comprising the inhibitor compound to a cell or subject. Examples of other kits known to those skilled in the art, such as kits with (preferably sterile) solvents for dissolving or suspending the inhibitory compound or composition prior to administering the compound or composition to a cell or subject. Should be construed to be included. Preferably, the subject is a human.

  As described above or discussed in the examples below, the disclosed compounds and methods include conventional chemical, cellular, histochemical, biochemical, molecular biology, microorganisms known to those skilled in the art. Science and in vivo technologies can be adopted. Such techniques are explained fully in the literature.

  Those skilled in the art will be able to produce and utilize the disclosed compounds using the foregoing description and the illustrative examples below without further explanation.

Processes for preparing compounds of formula I or for preparing intermediates useful in preparing compounds of formula I are provided as further examples. Intermediates useful for the preparation of compounds of formula I are also provided as further examples. These processes are provided as further examples and illustrated within this document, where the meaning of generic radicals is as described above unless otherwise limited. A general method for the preparation of the disclosed compounds is illustrated in Scheme 1 and Scheme 2 and illustrated in FIGS. 1A and 1B, respectively.

  The present invention will now be described with reference to the following examples and embodiments. Those skilled in the art will be able to produce and utilize the disclosed compounds using the foregoing description and the illustrative examples below without further explanation. Accordingly, the following examples are provided for illustrative purposes only, and are specifically pointed out preferred embodiments, and are not to be construed as limiting the remainder of the disclosure in any way. Accordingly, the examples should be construed to include any and all variations which become apparent as a result of the teaching provided herein.

  material. Synthetic chemicals were purchased from Aldrich Chemical Company (Milwaukee, Wis.), Sigma Chemicals (St. Louis, MO), and / or NovaBiochem Chemical Company (Leuverfingen, Switzerland), which is the highest quality available. And used without further purification. All reactions were carried out in an inert environment with nitrogen unless otherwise stated. All solvents were filtered through alumina (Activity 1) before use in the reaction. For thin layer chromatography (TLC), plates pre-coated with Merck silica gel F-254 and with an aluminum backing were used. For column chromatography, Merck Silica Gel 6 (230-400 mesh) or Silicycle Ultra Pure Silica Gel (230-400 mesh) was used. Nuclear magnetic resonance spectra were collected using a Varian Unity spectrometer at 300 MHz, chemical shifts were reported in ppm, and coupling constant J was reported in Hz. Mass spectrometry was collected using a Finnigan (model LCQ Classic) quadrupole ion trap mass spectrometer.

  N-Fmoc, O-TBS, Tyrosine OMe

Tyrosine OMe ester hydrochloride (5 g, 21.6 mmol) in H ₂ O (20 ml) was added to H ₂ O (10
K ₂ CO ₃ (5.97 g, 43.2 mmol) dissolved in ml) is added at 0 ° C. The precipitate is dioxane (40
Add FmocCl in small portions. The turbid mixture is stirred at 0 ° C. for 4 hours until complete as judged by TLC (4: 1 hexane: EtOAc). The reaction is extracted with EtOAc, dried over MgSO ₄ and evaporated. Crude O-Fmoc protected tyrosine and imidazole (4.4 g, 64.7 mmol) are dissolved in anhydrous CH ₂ Cl ₂ (50 ml). TBSCl (8.13 g, 54.0 mmol) dissolved in anhydrous CH ₂ Cl ₂ (20 ml) is added at 0 ° C. The mixture is stirred for 4 hours at room temperature until complete as judged by TLC (4: 1 hexane: EtOAc). The mixture is extracted with Et ₂ O, dried over MgSO ₄ and the solvent is evaporated under reduced pressure. Flash chromatography gave the product as a white solid (10.55 g, 86.5% yield). Rf (SiO ₂ in hexane 15% ethyl acetate) = 0.25.

  (2-R) -3- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -2- (9H-fluoren-9-ylmethoxycarbonylamino) -propionic acid methyl ester

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.19 (s, 6H), 1.00 (s, 9H), 3.06 (t, 2H, J = 5.6),
3.71 (s, 3H), 4.21 (t, 2H, J = 7.0), 4.31-4.49 (m, 2H), 4.65 (dd, 1H, J = 13.9,
7.9), 5.39 (t, 1H, J = 6.6), 6.77 (d, 2H, J = 8.1), 6.97 (d, 2H, J = 8.1), 7.32
(t, 2H, J = 7.5), 7.41 (t, 2H, J = 7.5), 7.58 (dd, 2H, J = 2.6, 6.9), 7.77 (d, 2H, J = 7.5). ¹³ C NMR (300 MHz, CDCl ₃ ) δ = -4.54, 18.05, 25.56, 37.36, 47.06, 52.13, 54.83, 66.80, 119.87, 120.05, 125.02, 124.94, 126.95, 127.59, 128.28, 130.18, 141.21, 143.66, 143.77, 154.67, 155.47, 171.95.MS (ESI) m / z = 532.0 (M + H) ⁺ , 100%).

  (2-S) -3- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -2- (9H-fluoren-9-ylmethoxycarbonylamino) -propionic acid methyl ester

  This product has spectral characteristics similar to its enantiomer.

  N-Boc or N-Fmoc, O-TBS, tyrosinal

N-Boc or N-Fmoc, O-TBS, tyrosine OMe (10.2 mmol) dissolved in anhydrous toluene (100 ml) was cooled to -78 ° C and DIBAL-H (1M in hexane, 30.5 ml, 30.5 mmol) is added by cannulation over 45 minutes. The reaction is stirred for an additional 5 minutes and quenched with MeOH. The mixture is removed from the cooling bath, a saturated aqueous Rochelle salt solution (150 ml) is added, and the mixture is stirred vigorously for 1.5 hours or until the phase is clear. The mixture is extracted with ether, and the ether containing extract is washed with brine, dried over MgSO ₄ and concentrated under reduced pressure to give the aldehyde as a glassy solid, which Use without further purification.

  [4- [4- (tert-butyl-dimethyl-silanyloxy) -phenyl] -3- (9H-fluoren-9-ylmethoxycarbonylamino) -trans-but-1-enyl] -phosphonic acid diethyl ester, or [ 4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3- (tert-butoxycarbonylamino) -trans-but-1-enyl] -phosphonic acid diethyl ester

Method A. In a solution of N-PG, O-TBS tyrosinal (10 mmol) in anhydrous toluene, according to the method by Xu, Y. et al. (J. Organic Chemistry, 1996, 61, 7697-7701), [(diethoxyphosphini Add Le) Mechiruiden] triphenylphosphonium filler down the (15 mmol) at room temperature, N ₂ below. The mixture is heated to 100 ° C. for 16 hours or until complete as judged by TLC (1: 1 Hexane: EtOAc). Upon completion, the solvent was removed under reduced pressure and the residue was subjected to flash chromatography (1: 1 Hexane: EtOAc to 100% EtOAc) to give the product as a pale yellow oil (66% yield). _{Rf (SiO 2, EtOAc) =} 0.61.

Method B. A solution of NaH (60% in mineral oil, 375 mg, 9.4 mmol) in THF (15 ml) cannulated with the appropriate tetra-ethyl diphosphonic acid (9.4 mmol) in THF (15 ml) at 0 ° C. Add by insertion. The mixture is stirred at 0 ° C. for 30 minutes and aldehyde dissolved in THF (25 ml) is added via cannulation. The mixture is left stirring for a further 30 minutes at 0 ° C. Excess NaH is quenched with saturated aqueous ammonium chloride and the aqueous layer is extracted with ethyl acetate. The organic layer is washed with brine, dried (MgSO ₄ ), evaporated to dryness and subjected to flash chromatography (1: 1 hexane: EtOAc to 100% EtOAc) to give the product as a pale yellow oil. To obtain (yield 43%). _{Rf (SiO 2, EtOAc) =} 0.61.

  (3R)-[4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3- (9H-fluoren-9-ylmethoxycarbonylamino) -trans-but-1-enyl] -phosphonic acid diethyl ester

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.16 (s, 6H), 0.97 (s, 9H), 1.28 (q, 6H, J = 8.8, 7.1), 2.83 (d, 2H, J = 6.1), 3.92 -4.05 (m, 4H), 4.17 (t, 2H, J = 7.0), 4.25-4.46
(m, 2H), 4.52-4.66 (m, 1H), 5.03-5.19 (m, 1H), 5.67 (apparent t, 1H, J = 18.0), 6.64-6.81 (m, 3H), 6.99 (d, 2H, J = 7.7), 7.33 (d, 2H, J = 7.3), 7.38 (d, 2H, J = 7.5), 7.53 (dd, 2H, J = 2.9, 7.0), 7.75 (d, 2H, J = 7.5). ¹³ C NMR (300 MHz, CDCl ₃ ) δ = -4.62, 16.16 (d, ³ J _{C, P} = 6.0 Hz), 17.97, 25.48, 39.58, 47.03, 54.02 (d, ³ J _{C, P} = 24.2 Hz), 61.59 (d, ² J _{C, P} = 6.0 Hz), 66.56, 117.13 (d, ¹ J _{C, P} = 186.7 Hz),
119.81, 119.95, 124.81, 124.89, 126.92, 127.56, 130.20, 141.15, 143.64, 151.32 (d, ² J _{C, P} = 6.0 Hz) ,, 151.38, 154.46, 155.39, 169.49.MS (ESI) m / z = 636.7 ((M + H) ⁺ , 100%).

  (3S)-[4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3- (9H-fluoren-9-ylmethoxycarbonylamino) -trans-but-1-enyl] -diethylphosphonate

  This product has spectral characteristics similar to its enantiomer.

  General procedure for Fmoc deprotection and acylation. Synthesis of diethyl {4- [4- (tert-butyl-dimethyl-silanyloxy) -phenyl] -3-acylamino-trans-but-1-enyl} -phosphonate

Dissolve diethyl [4- [4- (O-TBS) -phenyl] -3- (N-Fmoc) -trans-but-1-enyl] -phosphonate (1.3 g, 2.0 mmol) in DMF (10 ml). Add piperidine (10.0 mmol, 1 ml). The solution is stirred for 15 minutes at room temperature under N ₂ and then evaporated to dryness to give the free amine. Hunig's base (6.0 mmol, 1.1 ml) and acid chloride (2.4 mmol) are added to the amine dissolved in CH ₂ Cl ₂ (50 ml) and the mixture is stirred at room temperature under N ₂ . Upon completion as determined by TLC, the solvent is evaporated under reduced pressure and the residue is subjected to flash chromatography to give the product as a yellow oil (yield 60-80%).

  (3R)-{4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3-hexadecanoylamino-trans-but-1-enyl} -diethylphosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.14 (s, 6H), 0.84 (t, 3H, J = 6.8), 0.93 (s, 9H), 1.09-1.26 (m, 30H), 1.43-1.56 (m , 2H), 2.10 (t, 2H, J = 7.5), 2.79 (d, 2H, J = 6.8), 3.86-4.01 (m, 4H), 4.77-4.95 (m, 1H), 5.62 (apparent t, 1H, J = 19.5), 6.03 (d, 1H, J = 8.4), 6.58-6.76 (m, 3H), 6.98 (d, 2H, J = 8.4). 13 C NMR (300 MHz, CDCl 3) δ = -4.54, 14.02, 16.22 (d, ³ J _{C, P} = 6.0 Hz), 18.05, 25.56, 29.19, 29.27, 29.41, 29.57, 29.62, 31.84, 36.56, 39.45, 51.91 (d, ³ J _{C, P} = 22.2 Hz), 61.76 (d, ² J _{C, P} = 6.0 Hz), 116.91 (d, ¹ J _{C, P} = 187.4 Hz), 120.00, 130.18, 132.05, 151.64 (d, ² J _{C, P} = 6.0 Hz) , 154.48, 172.56.MS (ESI) m / z = 651.44 ((M + H) ⁺ , 100%).

  (3S)-{4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3-hexadecanoylamino-trans-but-1-enyl} -diethylphosphonate

  This product has spectral characteristics similar to its enantiomer.

(3R)-{4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3-tetradecanoylamino-trans-but-1-enyl} -diethylphosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.15 (s, 6H), 0.85 (t, 3H, J = 6.7), 0.95 (s, 9H), 1.15-1.29 (m, 26H), 1.46-1.59 (m , 2H), 2.11 (t, 2H, J = 7.3), 2.81 (d, 2H, J = 7.0), 3.88-4.06 (m, 4H), 4.81-4.94 (m, 1H), 5.60 (apparent t, 1H, J = 19.1), 5.84 (d, 1H, J = 8.6), 6.60-6.77 (m, 3H), 6.99 (d, 2H, J = 8.4). 13 C NMR (300 MHz, CDCl 3) δ = -4.52, 14.05, 16.25 (d, ³ J _{C, P} = 6.0 Hz), 18.08, 22.62, 25.56, 25.64, 29.19, 29.30, 29.43, 29.59, 31.86, 36.62, 39.42, 51.85 (d, ³ J _{C, P} = 22.2 Hz), 61.74 (t, ² J _{C, P} = 6.0 Hz), 116.94 (d, ¹ J _{C, P} = 187.4 Hz), 120.05, 128.92, 130.20, 151.61 (d, ² J _{C, P} = 6.0 Hz), 154.51, 172.56.MS (ESI) m / z = 623.41 ((M + H) ⁺ , 100%).

  (3S)-{4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3-tetradecanoylamino-trans-but-1-enyl} -diethylphosphonate

  This product has spectral characteristics similar to its enantiomer.

  (3R)-{4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3-dodecanoylamino-trans-but-1-enyl} -diethylphosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.13 (s, 6H), 0.82 (t, 3H, J = 7.0), 0.92 (s, 9H), 1.14-1.34 (m, 22H), 1.45-1.57 (m , 2H), 2.10 (t, 2H, J = 7.4), 2.78 (d, 2H, J = 7.0), 3.87-4.09 (m, 4H), 4.76-4.95 (m, 1H), 5.62 (apparent t, 1H, J = 18.4), 6.20 (d, 1H, J = 8.6), 6.57-6.78 (m, 3H), 6.98 (d, 2H, J = 8.4). 13 C NMR (300 MHz, CDCl 3) δ = -4.60, 13.97, 16.17 (d, ³ J _{C, P} = 6.0 Hz), 18.00, 22.54, 25.51, 29.14, 29.19, 29.35, 29.46, 29.51, 31.76, 36.48, 39.39, 51.94 (d, ³ J _{C, P} = 22.2 Hz), 61.70 (d, ² J _{C, P} = 6.0 Hz), 116.74 (d, ¹ J _{C, P} = 185.4 Hz), 119.92, 128.31, 130.12, 131.86, 151.66 (d, ² J _{C, P} = 6.1 Hz), 154.38, 172.56.

  (3R)-{4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3-decanoylamino-trans-but-1-enyl} -diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.14 (s, 6H), 0.83 (t, 3H, J = 6.4), 0.93 (s, 9H),
1.15-1.33 (m, 18H), 1.43-1.58 (m, 2H), 2.10 (t, 2H, J = 7.5), 2.78 (d, 2H, J = 6.6), 3.85-4.01 (m, 4H), 4.77 -4.92 (m, 1H), 5.61 (apparent t, 1H, J = 18.7), 6.20 (d, 1H, J = 8.6), 6.56-6.78 (m, 3H), 6.98 (d, 2H, J = 8.4 ¹³ C NMR (300 MHz, CDCl ₃ ) δ = -4.60, 13.91, 16.17 (d, ³ J _{C, P} = 6.0 Hz), 18.00, 22.46, 25.51, 25.59, 28.87, 29.06, 29.14, 29.22, 29.30 , 31.52, 36.48, 39.37, 51.88 (d, ³ J _{C, P} = 22.2 Hz),
61.67 (t, ² J _{C, P} = 6.0 Hz), 116.76 (d, ¹ J _{C, P} = 185.3 Hz), 119.92, 128.47, 130.12, 131.86, 151.66 (d, ² J _{C, P} = 6.0 Hz), 154.38, 172.56.

  (3R)-{4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3-octanoylamino-trans-but-1-enyl} -diethylphosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.13 (s, 6H), 0.85 (t, 3H, J = 6.4), 0.92 (s, 9H), 1.10-1.33 (m, 14H), 1.45-1.59 (m , 2H), 2.10 (t, 2H, J = 7.5), 2.79 (d, 2H, J = 6.7), 3.87-4.02 (m, 4H), 4.78-4.93 (m, 1H), 5.62 (apparent t, 1H, J = 18.5), 6.04 (d, 1H, J = 8.1), 6.59-6.77 (m, 3H), 6.99 (d, 2H, J = 8.6). 13 C NMR (300 MHz, CDCl 3) δ = -4.57, 13.99, 16.20 (d, ³ J _{C, P} = 6.0 Hz), 18.05, 22.49, 25.53, 25.61, 28.90, 29.19, 29.24, 29.32, 31.76, 36.54, 39.39, 51.88 (d, ³ J _{C, P} = 22.2 Hz), 61.70 (t, ² J _{C, P} = 6.0 Hz), 116.84 (d, ¹ J _{C, P} = 187.4 Hz), 119.97, 128.3, 130.15, 131.89, 151.64 (d, ² J _{C, P} = 6.0 Hz), 154.43, 172.56.

  (3R)-{4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3-hexanoylamino-trans-but-1-enyl} -diethylphosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.13 (s, 6H), 0.83 (t, 3H, J = 7.2), 0.92 (s, 9H), 1.14-1.33 (m, 10H), 1.44-1.59 (m , 2H), 2.11 (t, 2H, J = 7.5), 2.79 (d, 2H, J = 7.0), 3.85-4.04 (m, 4H), 4.77-4.95 (m, 1H), 5.62 (apparent t, 1H, J = 18.5), 6.44 (d, 1H, J = 8.1), 6.57-6.78 (m, 3H), 6.99 (d, 2H, J = 8.1). 13 C NMR (300 MHz, CDCl 3) δ = -4.60, 13.78, 16.15 (d, ³ J _{C, P} = 8.0 Hz), 18.00, 22.22, 25.27, 25.48, 31.25, 36.83, 39.42, 52.02 (d, ³ J _{C, P} = 22.2 Hz), 61.69 (t , ² J _{C, P} = 6.0 Hz), 116.70 (d, ¹ J _{C, P} = 187.4 Hz), 119.89, 128.31, 130.10, 131.83, 151.74 (d, ² J _{C, P} = 6.0 Hz), 154.35, 172.64 .

  General procedure for O-TBS deprotection. Synthesis of diethyl 3-acylamino-4- [4-hydroxy-phenyl] -3-acylamine-trans-but-1-enyl} -phosphonate.

TBAF (3 mmol) in {4- [4- (O-TBS) -phenyl] -3-acylamino-trans-but-1-enyl} -phosphonate diethyl ester (1 mmol) in THF (10 ml) and stir the mixture at room temperature, N ₂ below. Upon completion as judged by TLC, the solvent is evaporated under reduced pressure and the residue is subjected to flash chromatography to give the product as white crystals (yield 94-100%).

  (3R)-[3-Hexadecanoylamino-4- (4-hydroxy-phenyl) -trans-but-1-enyl] -diethylphosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.87 (t, 3H, J = 6.5), 1.15-1.36 (m, 30H), 1.49-1.64 (m, 2H), 2.15 (t, 2H, J = 7.7) , 2.72-2.89 (m, 2H), 3.89-4.06 (m, 4H), 4.84-4.97 (m, 1H), 5.65 (apparent t, 1H, J = 19.5), 6.03 (d, 1H, J = 8.4 ), 6.66-6.83 (m, 3H) , 6.97 (d, 2H, J = 7.9). 13 C NMR (300 MHz, CDCl 3) δ = 14.07, 16.22 (d, 3 J C, P
= 8.1 Hz), 22.65, 25.69, 29.24, 29.46, 29.67, 31.89, 36.67, 39.58, 52.07 (d, ³ J
_{C, P} = 22.2 Hz), 62.07 (q, ² J _{C, P} = 10.1, 6.1 Hz), 116.60 (d, ¹ J _{C, P} = 191.4 Hz), 115.62, 127.72, 130.28, 152.19 (d, ² J _{C, P} = 8.1 Hz), 156.22, 172.99.

  (3S)-[3-Hexadecanoylamino-4- (4-hydroxy-phenyl) -trans-but-1-enyl] -diethyl phosphonate

  This product has spectral characteristics similar to its enantiomer.

  (3R)-[3-Tetradecanoylamino-4- (4-hydroxy-phenyl) -trans-but-1-enyl] -diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.86 (t, 3H, J = 6.6), 1.14-1.32 (m, 26H), 1.49-1.63 (m, 2H), 2.16 (t, 2H, J = 7.6) , 2.73-2.89 (m, 2H), 3.90-4.07 (m, 4H), 4.85-4.98 (m, 1H), 5.65 (apparent t, 1H, J = 18.4), 5.80 (d, 1H, J = 8.5 ), 6.66-6.84 (m, 3H) , 6.97 (d, 2H, J = 8.3). 13 C NMR (300 MHz, CDCl 3) δ = 14.10, 16.24 (d, 3 J C, P
= 8.1 Hz), 22.65, 25.69, 29.03, 29.24, 29.49, 29.62, 29.67, 31.89, 36.70, 39.58, 52.02 (d, ³ J _{C, P} = 22.2 Hz), 62.20 (q, ² J _{C, P} = 10.0 , 6.0 Hz), 115.59, 116.59 (d, ¹ J _{C, P} = 189.4 Hz), 115.62, 126.68, 130.31, 152.17 (d, ² J _{C, P} = 6.0 Hz), 156.11,
172.99.MS (ESI) m / z = 510.2 ((M + H) ⁺ , 100%).

  (3S)-[3-Tetradecanoylamino-4- (4-hydroxy-phenyl) -trans-but-1-enyl] -diethyl phosphonate

  This product has spectral characteristics similar to its enantiomer.

  (3R)-[3-Dodecanoylamino-4- (4-hydroxy-phenyl) -trans-but-1-enyl] -diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.83 (t, 3H, J = 6.4), 1.05-1.32 (m, 22H), 1.49-1.66 (m, 2H), 2.10 (t, 2H, J = 7.7) , 2.69-2.86 (m, 2H), 3.87-4.04 (m, 4H), 4.78-4.96 (m, 1H), 5.61 (apparent t, 1H, J = 18.3), 5.80-5.99 (bs, 1H), 6.63-6.81 (m, 3H),
6.95 (d, 2H, J = 8.1). 13 C NMR (300 MHz, CDCl 3) δ = 14.05, 16.20 (d, 3 J C, P = 6.1 Hz), 22.59, 25.67, 29.19, 29.27, 29.41, 29.57 , 31.84, 36.62, 39.47, 52.07 (d, ³ J _{C, P} = 22.2 Hz), 62.05 (q, ² J _{C, P} = 10.1, 6.1 Hz), 115.57, 116.47 (d, ¹ J _{C, P} =
189.4 Hz), 128.60, 130.23, 152.17 (d, ² J _{C, P} = 6.0 Hz), 156.16, 173.04.

  (3R)-[3-Decanoylamino-4- (4-hydroxy-phenyl) -trans-but-1-enyl] -diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.86 (t, 3H, J = 6.6), 1.19-1.32 (m, 18H), 1.49-1.61 (m, 2H), 2.15 (t, 2H, J = 7.6) , 2.73-2.89 (m, 2H), 3.91-4.07 (m, 4H), 4.85-4.98 (m, 1H), 5.57- 5.76 (m, 2H), 6.66-6.83 (m, 3H), 6.97 (d, ¹³ C NMR (300 MHz, CDCl ₃ ) δ = 14.02, 16.24 (d, ³ J _{C, P} = 8.1 Hz), 22.57, 25.67, 28.92, 29.14, 29.24, 29.41, 31.62, 36.70 , 39.58, 51.96 (d, ³ J _{C, P} = 22.2 Hz), 62.10 (q, ² J _{C, P} = 11.0, 6.0 Hz), 115.59, 116.59 (d, ¹ J _{C, P} = 189.4 Hz), 115.62 , 126.70, 130.31, 152.15 (d, ² J _{C, P} = 6.1 Hz), 156.08, 172.96.

  (3R)-[3-Octanoylamino-4- (4-hydroxy-phenyl) -trans-but-1-enyl] -diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.85 (t, 3H, J = 6.5), 1.12-1.34 (m, 14H), 1.48-1.63 (m, 2H), 2.14 (t, 2H, J = 7.6) , 2.71-2.88 (m, 2H), 3.89-4.06 (m, 4H), 4.81-4.97 (m, 1H), 5.64 (apparent t, 1H, J = 18.7), 5.95 (d, 1H, J = 8.5 ), 6.64-6.82 (m, 3H) , 6.96 (d, 2H, J = 8.4). 13 C NMR (300 MHz, CDCl 3) δ = 14.05, 16.20 (d, 3 J C, P
= 6.1 Hz), 22.59, 25.67, 28.90, 29.11, 29.22, 29.38, 31.78, 36.62, 39.50, 52.07
(d, ³ J _{C, P} = 22.2 Hz), 62.05 (t, ² J _{C, P} = 7.1 Hz), 115.57, 116.49 (d, ¹ J _{C, P} = 187.4 Hz), 126.65, 130.26, 152.17 (d , ² J _{C, P} = 6.0 Hz), 156.14, 173.04.

  (3R)-[3-Hexanoylamino-4- (4-hydroxy-phenyl) -trans-but-1-enyl] -diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.84 (t, 3H, J = 6.9), 1.16-1.33 (m, 10H), 1.54 (p, 2H, J = 8.3, 7.5), 2.14 (t, 2H, J = 7.5), 2.73-2.82 (m, 2H), 3.87-4.05 (m, 4H), 4.80-4.95 (m, 1H), 5.64 (apparent t, 1H, J = 18.5), 6.17 (d, 1H , J = 8.5), 6.64-6.81 ( m, 3H), 6.95 (d, 2H, J = 8.4). 13 C NMR (300 MHz, CDCl 3) δ = 13.83, 16.18 (d, 3 J C, P = 8.1 Hz), 22.27, 25.35, 31.27, 36.51, 39.47, 52.18 (d, ³ J _{C, P} = 22.2 Hz), 62.07 (t, ² J _{C, P} = 7.1 Hz), 115.54, 116.44 (d, ¹ J _{C, P} = 187.4 Hz), 126.73, 130.20, 152.20 (d, ² J _{C, P} = 6.1 Hz), 156.14, 173.15.

  General procedure for ether linkage. Synthesis of diethyl (3-acylamino-4-pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl) -phosphonate.

Appropriate 3-acylamino-4- [4-hydroxy-phenyl] -3-acylamine-trans-but-1-enyl} -phosphonate diethyl (1 mmol) and substituted 2-methanesulfoxymethylpyridine (1.2 mmol) To what is dissolved in acetone, K ₂ CO ₃ (10 mmol) and 18-crown-6 (0.1 mmol) are added. The reaction mixture is refluxed for 16 hours until complete as judged by TLC.
Upon completion, the reaction was filtered, the solvent was evaporated under reduced pressure and flash chromatography (1% MeOH in EtOAc to 10% MeOH in EtOAc) gave the product as white crystals (yield 85-98). %).

  (3R)-(3-Hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl ) -Diethylphosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.87 (t, 3H, J = 6.5), 1.15-1.35 (m, 30H), 1.45-1.57 (m, 2H), 2.10 (t, 2H, J = 7.4) , 2.81 (apparent d, 2H, J = 7.0), 3.87-4.02 (m, 4H), 4.39 (q, 2H, J = 8.0), 4.80-4.92 (m, 1H), 5.09 (s, 2H), 5.63 (ddd, 1H, J = 19.5, 17.1, 1.65), 6.03 (d, 1H, J = 8.6), 6.67 (ddd, 1H, J = 21.0, 18.0, 5.1), 6.75 (dd, 1H, J = 5.8 , 2.5), 6.86 (d, 2H, J = 8.6), 7.03-7.10 (m, 3H), 8.42 (d, 1H,
¹³ C NMR (300 MHz, CDCl ₃ ) δ = 13.94, 14.05, 16.17 (d, ³ J _{C, P} = 6.0 Hz), 20.86, 22.54, 25.59, 28.92, 29.24, 29.38, 29.51, 29.57 , 31.78, 36.51, 39.39, 51.91 (d, ³ J _{C, P} = 22.2 Hz), 61.70 (d, ² J _{C, P} = 5.0 Hz), 64.79 (q, ² J _{C, F} = 36.26), 70.16, 107.21, 109.00, 114.74, 117.01 (d, ¹ J _{C, P} = 185.3 Hz), 129.22, 130.31, 150.72, 151.45 (d, ² J _{C, P} = 6.0 Hz), 157.05, 159.66, 160.04, 172.51. MS ( ESI) m / z = 727.5
((M + H) ⁺ , 100%).

  (3S)-(3-Hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl ) -Diethylphosphonate

  This product has spectral characteristics similar to its enantiomer.

  (3R)-(3-Tetradecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl ) -Diethylphosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.86 (t, 3H, J = 6.7), 1.13-1.35 (m, 26H), 1.46-1.60 (m, 2H), 2.12 (t, 2H, J = 7.4) , 2.84 (d, 2H, J = 7.0), 3.91-4.07 (m, 4H), 4.41 (q, 2H, J = 7.9), 4.83-4.97 (m, 1H), 5.12 (s, 2H), 5.52 ( d, 1H, J = 8.4), 5.65
(ddd, 1H, J = 18.0, 17.0, 1.8), 6.70 (ddd, 1H, J = 21.1, 17.0, 5.1), 6.78 (dd, 1H, J = 5.3, 2.4), 6.90 (d, 2H, J = 8.8), 7.06-7.11 (m, 3H ), 8.45 (d, 1H, J = 5.7). 13 C NMR (300 MHz, CDCl 3) δ = 14.05, 16.35 (d, 3 J C, P = 6.0 Hz) , 22.62, 25.61,
29.16, 29.30, 29.43, 29.57, 31.84, 36.64, 39.42, 51.80 (d, ³ J _{C, P} = 22.2 Hz), 61.76 (d, ² J _{C, P} = 6.0 Hz), 64.85 (q, ² J _{C, F} = 36.3), 70.19, 107.23, 109.08, 114.82,
117.13 (d, ¹ J _{C, P} = 187.3 Hz), 129.06, 130.28, 130.39, 150.80, 151.40 (d, ² J _{C, P} =
6.0 Hz), 157.13, 159.69, 159.98, 164.10, 172.51.MS (ESI) m / z = 699.4 ((M + H) ⁺ , 100%).

  (3S)-(3-Tetradecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl ) -Diethylphosphonate

  This product has spectral characteristics similar to its enantiomer.

  (3R)-(3-dodecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl) -Diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.86 (t, 3H, J = 6.2), 1.14-1.43 (m, 22H), 1.48-1.62 (m, 2H), 2.12 (t, 2H, J = 7.4) , 2.84 (d, 2H, J = 6.8), 3.91-4.08 (m, 4H), 4.42 (q, 2H, J = 7.9), 4.85-4.97 (m, 1H), 5.14 (s, 2H), 5.44 ( d, 1H, J = 8.4), 5.65
(ddd, 1H, J = 18.1, 17.1, 1.7), 6.69 (ddd, 1H, J = 20.6, 16.8, 4.8), 6.79 (dd, 1H, J = 6.0, 2.6), 6.89 (d, 2H, J = 8.8), 7.05-7.16 (m, 3H ), 8.45 (d, 2H, J = 5.7). 13 C NMR (300 MHz, CDCl 3) δ = 14.02, 16.25 (d, 3 J C, P = 6.0 Hz) , 22.59, 25.61,
29.16, 29.24, 29.30, 29.41, 29.57, 31.84, 36.64, 39.39, 51.80 (d, ³ J _{C, P} = 22.2 Hz), 61.76 (d, ² J _{C, P} = 6.0 Hz), 64.85 (q, ² J _{C, F} = 36.3), 70.14, 107.26, 109.10, 114.82, 117.11 (d, ¹ J _{C, P} = 187.4 Hz), 129.06, 130.39, 130.84, 150.72, 151.40 (d, ² J _{C, P} = 6.0 Hz) , 157.10, 160.25, 166.45, 172.51.

  (3R)-(3-decanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl) -Diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.84 (t, 3H, J = 6.2), 1.14-1.31 (m, 18H), 1.44-1.60 (m, 2H), 2.11 (t, 2H, J = 7.6) , 2.82 (d, 2H, J = 6.4), 3.89-4.06 (m, 4H), 4.40 (q, 2H, J = 7.9), 4.83-4.97 (m, 1H), 5.10 (s, 2H), 5.64 ( Apparent t, 1H, J = 18.4), 5.83 (d, 1H, J = 8.0), 6.59-6.81 (m, 2H), 6.88 (d, 2H, J = 8.4), 7.04-7.12 (m, 3H) , 8.44 (d, 1H, J = 5.7). 13 C NMR (300 MHz, CDCl 3) δ = 13.97, 16.24 (d, 3 J C, P = 8.0 Hz), 22.51, 25.61, 28.92, 29.08, 29.62, 31.57, 36.59, 39.39, 51.86 (d, ³ J _{C, P} = 22.2 Hz), 61.84 (d, ² J _{C, P} = 6.0 Hz), 64.85 (q, ² J _{C, F} = 36.3), 70.11, 107.26 , 109.08, 114.79, 117.02 (d, ¹ J _{C, P} = 187.4 Hz), 129.14, 130.39, 150.72, 151.48 (d, ² J _{C, P} = 6.0 Hz), 157.07, 159.64, 164.12, 172.56.

  (3R)-(3-Octanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl) -Diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.85 (t, 3H, J = 6.6), 1.18-1.31 (m, 14H), 1.48-1.57 (m, 2H), 2.12 (t, 2H, J = 7.5) , 2.84 (d, 2H, J = 6.8), 3.90-4.07 (m, 4H), 4.41 (q, 2H, J = 7.9), 4.84-4.97 (m, 1H), 5.13 (s, 2H), 5.57- 5.72 (m, 2H), 6.70 (ddd, 1H, J = 21.4, 16.8, 4.8), 6.80 (dd, 1H, J = 5.7, 2.6), 6.90 (d, 2H, J = 8.6), 7.05-7.12 ( m, 3H), 8.46 (d , 1H, J = 5.7). 13 C NMR (300 MHz, CDCl 3) δ = 14.05, 16.28 (d, 3 J C, P = 6.0 Hz), 22.62, 25.64, 29.24, 29.67, 31.81, 36.70, 39.42, 51.83
(d, ³ J _{C, P} = 22.2 Hz), 61.82 (t, ² J _{C, P} = 6.0 Hz), 65.14 (q, ² J _{C, F} = 36.3), 70.14,
107.31, 109.16, 114.87, 117.13 (d, ¹ J _{C, P} = 187.4 Hz), 129.06, 129.62, 130.44, 150.74, 151.42 (d, ² J _{C, P} = 6.0 Hz), 157.15, 159.66, 164.20, 172.54.

  (3R)-(3-Hexanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl) -Diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.86 (t, 3H, J = 6.9), 1.16-1.35 (m, 10 H), 1.54 (p, 2H, J = 7.5), 2.13 (t, 2H, J = 7.4), 2.84 (d, 2H, J = 7.0), 3.92-4.08 (m, 4H), 4.42 (q, 2H, J = 7.9), 4.84-4.97 (m, 1H), 5.13 (s, 2H) , 5.58-5.78 (m, 2H), 6.71 (ddd, 1H, J = 22.4, 16.9, 4.8), 6.80 (dd, 1H, J = 5.9, 2.6), 6.90 (d, 2H, J = 8.6), 7.09 (apparent d, 3H, J = 8.6) , 8.46 (d, 1H, J = 5.7). 13 C NMR (300 MHz, CDCl 3) δ = 13.83, 16.21 (d, 3 J C, P = 6.0 Hz) , 22.30, 25.29, 29.65, 31.27, 36.59, 39.37, 51.83 (d, ³ J _{C, P} = 22.2 Hz), 61.87 (d, ² J _{C, P} = 6.0 Hz), 64.87 (q, ² J _{C, F} = 36.3), 70.11, 107.29, 109.16, 114.85, 117.07 (d, ¹ J _{C, P} = 187.4 Hz), 129.08, 130.42,
150.69, 151.49 (d, ² J _{C, P} = 6.0 Hz), 157.13, 159.64, 167.14, 172.56.

  (3R)-(3-Benzylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl)- Diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 1.19-1.32 (m, 6H), 2.98 (apparent d, 2H, J = 6.9), 3.92-4.08 (m, 4H), 4.39 (q, 2H, J = 7.9), 5.12 (s, 2H), 5.72 (ddd, 1H, J = 21.4,
17.1, 1.2), 6.58 (d, 1H, J = 8.4), 6.75-6.68 (m, 2H), 6.91 (d, 2H, J = 8.6), 7.0
9 (d, 1H, J = 2.4), 7.14 (d, 2H, J = 8.4), 7.35-7.57 (m, 4H), 7.72 (d, 2H, J = 7.0), 8.47 (d, 1H, J = ^{5.7). 13 C NMR (300} MHz, CDCl 3) δ = 16.24 (d, 3 J C, P = 8.1 Hz), 39.39, 52.58 (d, 3 J C, P = 22.2 Hz), 61.91 (d, 2 J _{C, P} = 6.0 Hz), 64.85 (q, ² J _{C, F} = 36.3), 70.03, 107.26, 109.21, 114.90, 117.32 (d, ¹ J _{C, P} = 187.4 Hz), 126.92, 128.52, 129.06, 130.50, 131.65, 134.00, 150.64, 151.38 (d, ² J _{C, P} = 4.0 Hz), 157.13, 159.61, 164.20, 172.51.

  (3R)-(3-Hexadecanoylamino-4- {4- [4- (pentoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl) -diethylphosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.87 (t, 3H, J = 6.6), 0.93 (t, 3H, J = 6.8), 1.15-1.36 (m, 30H), 1.37-1.49 (m, 4H) , 1.49-1.60 (m, 2H), 2.79 (p, 2H, J = 6.9), 2.13 (t, 2H, J = 7.5), 2.85 (dd, 2H, J = 1.7, 6.6), 3.96-4.07 (m , 4H), 4.12 (q, 2H,
J = 7.3), 4.85-4.98 (m, 1H), 5.10 (s, 2H), 5.37 (d, 2H, J = 8.6), 5.65 (ddd, 1H, J = 19.3, 17.1, 1.6), 6.63-6.80 (m, 2H), 6.91 (d, 2H, J = 8.6), 7.02 (d, 1H, J = 2.4), 7.08 (d, 2H, J = 8.6), 8.38 (d, 1H, J = 5.7). ¹³ C NMR (300 MHz, CDCl ₃ ) δ = 13.91, 14.07, 16.39 (d, ³ J _{C, P} = 6.0 Hz), 22.35, 22.65, 25.64, 28.02, 28.55, 29.22, 29.32, 29.46, 29.62, 29.67, 31.89, 36.72, 39.39, 51.78 (d, ³ J _{C, P} = 22.2 Hz), 61.83 (t, ² J _{C, P} = 6.0 Hz), 68.03 (q, ² J _{C, F} = 36.3), 70.56, 107.63 , 109.21, 114.95, 117.27 (d, ¹ J _{C, P} = 187.4 Hz), 128.71, 130.36, 150.37, 151.40 (d, ² J _{C, P} = 6.0 Hz), 166.07, 172.46

  (3R)-{3-Hexadecanoylamino-4- [4- (4-methoxy-3,5-dimethyl-pyridin-2-ylmethoxy) -phenyl] -trans-but-1-enyl} -diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.86 (t, 3H, J = 6.7), 1.15-1.36 (m, 26H), 1.47-1.62 (m, 2H), 2.13 (t, 2H, J = 7.6) 2.31 (s, 3H), 2.83 (d, 2H, J = 6.6), 3.77 (s, 3H), 3.90-4.09 (m, 4H), 4.84-4.97 (m, 1H) , 5.10 (s, 2H), 5.56-5.71 (m, 2H), 6.70 (ddd, 1H, J = 21.0, 17.0, 5.1), 6.93 (d, 2H, J = 8.6), 7.05 (d, 2H, J = 8.6), 8.22 (s, 1H). 13 C NMR (300 MHz, CDCl 3) δ = 10.90, 13.33, 14.07,
16.30 (d, ³ J _{C, P} = 6.0 Hz), 22.65, 25.64, 29.22, 29.30, 29.46, 29.65, 31.89, 36.70, 39.39, 51.78 (d, ³ J _{C, P} = 22.2 Hz), 59.85, 61.80 ( d, ² J _{C, P} = 6.0 Hz), 70.83, 114.95, 117.16 (d, ¹ J _{C, P} = 187.4 Hz), 128.49, 130.26, 149.01, 151.49 (d, ² J _{C, P} = 4.0 Hz), 154.11, 157.79, 172.48.MS (ESI) m / z = 687.1 ((M + H) ⁺ , 100%).

  General procedure for the reduction of vinyl phosphonate. Synthesis of diethyl {3-acylamino-[(4-pyridin-2-ylmethoxy) -phenyl] -butyl} -phosphonate.

  (3-Acylamino-4-pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl) -phosphonic acid diethyl (0.1 mmol) dissolved in EtOH, 10% Pd / C (0.01 mmol) And the solution is left stirring under a hydrogen balloon for 2 hours at room temperature. Upon completion, the solution is filtered over celite and volatiles are removed under reduced pressure. The residue is subjected to flash chromatography (1-10% MeOH: EtOAc) to give the product as colorless crystals (yield 90-98%).

  (1R)-(3-Hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -butyl) -diethylphosphonate

¹ H NMR (300MHz, CD ₃ OD) δ = 0.79 (t, 3H, J = 6.6), 1.04-1.20 (m, 30H), 1.38 (p, 2H, J = 7.25), 1.60-1.75 (m, 2H ), 2.00 (t, 2H, J = 7.0), 2.50-2.71 (m, 2H), 3.88-4.03 (m, 7H), 4.61 (q, 2H, J = 8.4), 5.00 (s, 2H), 6.84 (d, 2H, J = 8.8), 6.92 (ddd, 1H, J = 2.6, 5.9), 7.05 (d, 2H, J = 8.8), 7.14 (d, 1H, J = 2.6), 7.73 (d, 1H , J = 9.0), 8.81 ( d, 1H, J = 5.7). 13 C NMR (300 MHz, CD 3 OD) δ = 14.41, 16.72 (d, 3 J C, P = 12.0 Hz), 21.97, 23.71. 23.87, 27.10, 28.30 (d, ² J _{C, P} = 4.03 Hz), 30.17, 30.49, 30.62, 30.78, 33.05, 37.27, 40.88, 50.53 (d, ³ J _{C, P} = 16.1 Hz), 61.69 (d, ² J _{C, P} = 10.1 Hz), 64.90 (d, ² J _{C, F} = 36.3 Hz), 109.60, 110.56, 115.66, 115.74, 131.42, 132.52, 151.56, 158.35, 160.80, 161.42, 176.16.MS (ESI) m / z = 729.4 ((M + H) ⁺ , 100%).

  (1S)-(3-Hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -butyl) -diethylphosphonate

  This product has spectral characteristics similar to its enantiomer.

  (1R)-(3-Tetradecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -butyl) -diethylphosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.86 (t, 3H, J = 6.6), 1.15-1.34 (m, 28H), 1.46-1.64 (m, 2H), 1.66-1.89 (m, 2H), 2.10 (t, 2H, J = 7.5), 2.62-2.83 (m, 2H), 3.94-4.20 (m, 7H), 4.41 (q, 2H, J = 7.9), 5.13 (s, 2H), 5.74 (d, 1H, J = 8.8), 6.78 (ddd, 1H, J = 2.6, 5.7), 6.89 (d, 2H, J = 8.1), 7.08 (apparent d, 3H, J = 8.6), 8.46
(d, 1H, J = 5.7 ). 13 C NMR (300 MHz, CD 3 OD) δ = 14.05, 16.36 (d, 3 J C, P = 6.0 Hz), 22.62, 23.13. 25.72, 26.44 (d, 2 J _{C, P} = 4.03 Hz), 29.22, 29.27, 29.32, 29.43, 29.59, 31.84, 36.86, 40.04, 50.65 (d, ³ J _{C, P} = 16.1 Hz), 61.63 (d, ² J _{C, P} = 8.0 Hz),
64.85 (d, ² J _{C, F} = 36.3 Hz), 107.18, 109.16, 114.71, 120.75, 120.96, 130.39, 150.69, 158.86, 159.82, 173.07.

  (1S)-(3-Tetradecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -butyl) -diethylphosphonate

  This product has spectral characteristics similar to its enantiomer.

  (1R)-{3-Hexadecanoylamino-4- [4- (4-methoxy-3,5-dimethyl-pyridin-2-ylmethoxy) -phenyl] -butyl} -diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.85 (t, 3H, J = 6.6), 1.15-1.32 (m, 30H), 1.47-1.59 (m, 2H), 1.66-1.86 (m, 3H), 2.05 -2.13 (m, 2H), 2.10 (t, 2H, J = 7.5), 2.25 (s, 3H). 2.30 (s, 3H), 2.60-2.81 (m, 2H), 3.76 (s, 3H), 3.96 -4.18 (m, 6H), 5.10 (s, 2H), 5.70 (d, 1H, J = 8.6), 6.92 (d, 2H, J = 8.6), 7.06 (d, 2H, J = 8.6), 8.22
^{(s, 1H). 13 C} NMR (300 MHz, CD 3 OD) δ = 10.87, 13.30, 14.02, 16.36 (d, 3 J C, P = 6.0 Hz), 22.59, 23.18, 25.69, 26.42 (d, 2 J _{C, P} = 4.0 Hz), 29.22, 29.30, 29.57, 29.62, 31.84, 36.83, 50.43 (d, ³ J _{C, P} = 16.1 Hz), 59.83, 61.59 (d, ² J _{C, P} = 8.1 Hz) ,
70.72, 114.79, 129.83, 130.23, 148.85, 154.13, 157.47, 164.36, 172.99.MS (ESI) m / z = 689.0 ((M + H) ⁺ , 100%).

  General procedure for ether phosphonate deprotection. Synthesis of {3-acylamino-[(4-pyridin-2-ylmethoxy) -phenyl] -trans-but-1-enyl} -phosphonate.

Method A. To a solution of diethyl (3-acylamino-4-pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl} -phosphonate (0.1 mmol) in CH ₂ Cl ₂ , add TMSBr (1.0 mmol). The solution is then left stirring for 2 hours at room temperature The volatiles are removed under reduced pressure and water (2
mL). The solution is stirred for 10 minutes, extracted with ether and the aqueous layer is evaporated under reduced pressure. The residue is precipitated from either water or methanol and ether, then filtered and washed with water and ether to give the product as white crystals.

Method B. (3-Acylalkenylamino-4-pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl} -phosphonate diethyl (0.1 mmol) in CH ₂ Cl ₂ was dissolved in pyridine (1.0 mmol ) Is added and TMSBr (0.5 mmol) is added and the solution is left to stir at room temperature for 6 hours, volatiles are removed under reduced pressure and 1N aqueous NaOH (2 mL) is added. And then extract with Et ₂ O to remove excess pyridine, acidify the solution with 1N HCl (pH = 1), filter the precipitate, wash off with water and ether, and wash the product with white As crystals.

  (3R)-(3-Hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl ) -Phosphonic acid (vpc51299)

¹ H NMR (300MHz, CD ₃ OD) δ = 0.71 (t, 3H, J = 6.7), 1.01-1.18 (m, 24H), 1.30-1.44 (m, 2H), 1.99 (t, 2H, J = 7.6 ), 2.58-2.74 (m, 2H), 4.51-4.61 (m, 1H), 4.72 (q, 2H, J = 7.8), 5.25 (s, 2H), 5.68 (apparent t, 1H, J = 18.0) , 6.37 (ddd, 1H, J = 22.4, 17.1, 4.6), 6.83 (d, 2H, J = 8.4), 7.02 (d, 2H, J = 8.4), 7.37 (bs, 1H), 7.54 (bs, 1H ), 8.64 (bs, 1H) . 13 C NMR (300 MHz, CDCl 3) δ = 14.44, 23.73, 27.05,
30.22, 30.46, 30.60, 30.78, 33.05, 37.06, 40.32, 54.15 (t, ³ J _{C, P} = 6.05 Hz), 67.35 (t, ² J _{C, F} = 18.1 Hz), 112.22, 113.39, 115.96, 119.96 ( d, ¹ J _{C, P} = 167.2 Hz), 122.50, 131.72, 132.79, 145.79, 149.12 (d, ² J _{C, P} = 6.0 Hz), 157.60, 170.79, 175.76. ³¹ P NMR (121.5 MHz, CD ₃ OD : TFA) δ = 16.53. ¹⁹ F NMR (282 MHz, CD ₃ OD: TFA) δ = -75.71 (t, J = 7.93 Hz, 3F) .HRMS (ESI) m / z = detected value 671.3444 (calculated value 671.3437 EA detected value: C 54.51, H 7.18, N 3.70 (calculated value: C 60.88, H 7.51, N 4.18)

  (3S)-(3-Hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl ) -Phosphonic acid (vpc52156)

  This product has spectral characteristics similar to its enantiomer.

  (3R)-(3-Tetradecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl ) -Phosphonic acid (vpc52184)

¹ H NMR (300MHz, DMSO) δ = 0.83 (t, 3H, J = 6.6), 1.09 (bs, 2H), 1.12-1.28 (m,
20H), 1.31-1.41 (m, 2H), 1.97-2.04 (m, 2H), 2.53-2.84 (m, 2H), 4.51-4.63 (m, 1H), 5.11 (q, 2H, J = 8.6), 5.24 (s, 2H), 5.71 (apparent t, 1H, J = 18.0), 6.41 (ddd,
1H, J = 20.8, 17.3, 4.2), 6.96 (d, 2H, J = 8.3), 7.17 (d, 2H, J = 8.3), 7.45 (d, 1H, J = 4.17), 7.56 (s, 1H) , 8.72 (d, 2H, J = 6.1). 13 C NMR (300 MHz, DMSO) δ = 13.93, 22.08, 25.30, 28.52, 28.70, 28.81, 28.91, 29.00, 29.04, 29.06, 31.17, 31.28, 35.31, 65.08 (q, ² J _{C, F} = 34.6), 110.51, 110.98, 114.42, 120.28, 121.0 (d, ¹ J _{C, P} = 182.6 Hz), 124.48, 130.28, 131.41, 146.96 (d, ² J _{C, P} = 15.7 Hz), 155.97,
171.53. HRMS (ESI) m / z = 643.3129 (M ⁺ , C ₃₂ H ₄₆ F ₃ N ₂ O ₆ P Required 643.3124). Calculated for C ₃₂ H ₄₈ F ₃ N ₂ O ₆ PBr ₂ : C, 47.77; H, 6.01; N, 3.48. Detected values: C, 47.80; H, 5.77; N,
3.46.

  (3S)-(3-Tetradecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl ) -Phosphonic acid (vpc52157)

  This product has spectral characteristics similar to its enantiomer.

  (3R)-(3-dodecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl) -Phosphonic acid (vpc52172)

¹ H NMR (300MHz, DMSO) δ = 0.83 (t, 3H, J = 6.9), 1.07 (bs, 2H), 1.12-1.27 (m,
16H), 1.35 (p, 2H, J = 7.3), 1.93-2.04 (m, 2H), 2.55-2.84 (m, 2H), 4.56 (bs, 1H), 4.94 (q, 2H, J = 8.7), 5.10 (s, 2H), 5.71 (apparent t, 1H, J = 18.4), 6.41 (ddd, 1H, J = 22.4, 17.3, 4.5), 6.93 (d, 2H, J = 6.9), 7.07-7.17 ( m, 3H), 7.24 (s, 1H), 7.90 (d, 1H, J = 8.65), 8.50 (d, 2H, J = 5.1).

  (3R)-(3-decanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl) -Phosphonic acid (vpc52173)

¹ H NMR (300MHz, DMSO) δ = 0.82 (t, 3H, J = 6.4), 1.08 (bs, 2H), 1.12-1.28 (m,
12H), 1.30-1.40 (m, 2H), 1.94-2.06 (m, 2H), 2.53-2.85 (m, 2H), 4.56 (bs, 1H), 4.95 (q, 2H, J = 8.3), 5.11 ( s, 2H), 5.71 (apparent t, 1H, J = 18.0), 6.41 (ddd, 1H, J = 22.3, 17.3, 3.6), 6.93 (d, 2H, J = 7.4), 7.14 (d, 2H, J = 7.0), 7.25 (s , 1H), 7.92 (d, 1H, J = 8.7), 8.51 (s, 1H). 13 C NMR (300 MHz, DMSO) δ = 13.90, 22.07, 25.28, 28.45, 31.12 , 35.35, 64.19 (q, ² J _{C, F} = 34.6), 69.30, 108.75, 109.64, 114.36, 121.04 (d, ¹ J _{C, P} = 181.0 Hz), 124.75, 131.19, 130.88, 146.92 (d, ² J _{C, P} = 6.3 Hz), 156.38, 156.97, 164.32, 171.53.HRMS (ESI) m / z = 587.2483 (M ⁺ , C ₂₈ H ₃₉ F ₃ N ₂ O ₆ P required value 587.2498).

  (1R)-(3-Octanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl) -Phosphonic acid (vpc52178)

¹ H NMR (300MHz, DMSO) δ = 0.82 (t, 3H, J = 6.4), 1.08-1.29 (m, 8H), 1.29-1.44
(m, 2H), 2.00 (t, 2H, J = 6.3), 2.55-2.85 (m, 2H), 4.44-4.68 (m, 2H), 4.94 (q,
2H, J = 8.8), 5.10 (s, 2H), 5.71 (apparent t, 1H, J = 17.6), 6.41 (apparent t, 1H,
J = 19.4), 6.93 (d, 2H, J = 7.7), 7.14 (d, 2H, J = 7.7), 7.24 (s, 1H), 7.93 (d, 1H, J = 7.5), 8.51 (bs, 1H ¹³ C NMR (300 MHz, DMSO) δ = 13.89, 22.06, 24.54, 25.26, 28.47, 28.71, 28.84, 35.33, 51.68 (d, ³ J _{C, P} = 20.2 Hz), 64.50 (t, ² J _{C , F} =
6.1 Hz), 69.47, 112.52, 113.27, 114.34, 118.45 (d, ¹ J _{C, P} = 172.4 Hz), 124.35, 130.18, 130.84, 135.54, 146.99 (d, ² J _{C, P} = 6.0 Hz), 156.46, 171.01, 171.65.

  (3R)-(3-Hexanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl) -Phosphonic acid (vpc52183)

¹ H NMR (300MHz, DMSO) δ = 0.80 (t, 3H, J = 6.9), 0.99-1.14 (m, 2 H), 1.14 -1.29 (m, 2H), 1.30-1.46 (m, 2H), 1.92 -2.10 (m, 2H) .2.55-2.88 (m, 2H), 4.50-4.62 (m, 1H), 5.02-5.19 (m, 2H), 5.26 (s, 2H), 5.71 (apparent t, 1H, J = 17.5), 6.41 (apparent t, 1H, J = 19.2), 6.96 (d, 2H, J = 7.1), 7.18 (d, 2H, J = 6.5), 7.43-7.52 (m, 1H), 7.58 (d, 1H, J = 5.8 ), 7.95 (d, 1H, J = 8.1), 8.72 (s, 1H). 13 C NMR (300 MHz, DMSO) δ = 13.83, 21.81, 24.94, 30.68, 32.54, 35.30 , 51.72 (d, ³ J _{C, P} =
22.2 Hz), 65.32 (t, ² J _{C, F} = 34.2), 67.08, 110.65, 111.15, 114.45, 121.50 (d, ¹ J _{C, P} = 178.7 Hz), 130.28, 131.45, 146.67, 146.96 (d, ² J _{C, P} = 5.8 Hz), 155.95, 166.95, 171.52.

  (3R)-(3-Benzylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl)- Phosphonic acid (vpc52206)

¹ H NMR (300MHz, CDCl ₃ ) δ = 2.84-3.10 (m, 2H), 4.93 (q, 2H, J = 7.8), 5.31 (s,
2H), 5.74-6.00 (m, 1H), 6.70 (apparent t, 1H, J = 17.6), 7.01 (d, 2H, J = 7.5), 7.27 (d, 2H, J = 7.7), 7.36-7.55 (m, 4H), 7.62 (apparent s, 1H), 7.72 (d , 2H, J = 7.5), 8.60 (d, 1H, J = 6.0). 13 C NMR (300 MHz, CDCl 3) δ = 40.31 , 55.07 (d, ³ J _{C, P} = 22.2 Hz), 62.56, 67.26 (d, ² J _{C, F} = 36.3), 106.66, 110.02, 116.16, 118.34 (d, ¹
J _{C, P} = 187.4 Hz), 128.48, 129.71, 131.87, 132.91, 133.10, 135.72, 151.87 (d, ² J _{C, P} = 4.0 Hz), 157.91, 159.61, 169.96, 170.28.HRMS (ESI) m / z = 537.1397 (M ⁺ , C ₂₅ H ₂₅ F ₃ N ₂ O ₆ P Required 537.1402).

  (1R) (3-Hexadecanoylamino-4- {4- [4- (pentoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but-1-enyl) -phosphonic acid (vpc52071)

¹ H NMR (300MHz, CD ₃ OD) δ = 0.89 (t, 3H, J = 6.7), 0.96 (t, 3H, J = 7.1), 1.15-1.35 (m, 26H), 1.35-1.56 (m, 6H ), 1.88 (p, 2H, J = 6.7), 2.12 (t, 2H, J = 7.5),
2.70-2.96 (m, 2H), 4.33 (t, 2H, J = 6.4), 4.68-4.77 (m, 1H), 5.33 (s, 2H), 5.76
(Apparent t, 1H, J = 17.8), 6.61 (ddd, 1H, J = 21.1, 16.7, 4.9), 7.00 (d, 2H, J = 8.2), 7.22 (d, 2H, J = 8.6), 7.89 (d, 1H, J = 4.8), 7.53 (s, 1H), 8.54 (d, 1H, J
= 6.4).

  (3R)-{3-Hexadecanoylamino-4- [4- (4-methoxy-3,5-dimethyl-pyridin-2-ylmethoxy) -phenyl] -trans-but-1-enyl} -phosphonic acid ( vpc51304)

¹ H NMR (300MHz, CDCl ₃ / CD ₃ OD) δ = 0.82 (t, 3H, J = 6.6), 1.15-1.33 (m, 24H), 1.42-1.55 (m, 2H), 2.05-2.17 (m, 2H), 2.35 (s, 3H) .2.44 (s, 3H), 2.78 (d, 2H, J = 6.0), 3.84-3.98 (m, 2H), 4.07 (s, 3H), 4.66-4.77 (m, 1H), 5.30 (s, 2H), 5.62 (apparent t, 1H, J = 18.2), 6.54 (apparent t, 1H, J = 18.6), 7.07 (d, 2H, J = 8.6),
7.10 (d, 2H, J = 7.5), 8.58 (s, 1H). 13 C NMR (300 MHz, DMSO) δ = 10.60, 13.69, 13.94, 22.06, 25.26, 28.50, 28.68, 28.79, 29.03, 31.27, 35.31 , 50.71 (d, ³ J _{C, P} = 12.0 Hz), 58.41, 60.12, 70.54, 114.60, 118.13 (d, ¹ J _{C, P} = 181.3 Hz), 124.35, 130.23, 149.58 (d, ² J _{C, P} = 6.0 Hz), 155.95, 159.13, 171.75.HRMS (ESI) m / z = 631.3870 (M ⁺ , C ₃₅ H ₅₆ N ₂ O ₆ P Required 631.3876).

  (1R)-{3-Hexadecanoylamino-4- [4- (4-methoxy-3,5-dimethyl-pyridin-2-ylmethoxy) -phenyl] -butyl} -phosphonic acid (vpc52007)

¹ H NMR (300MHz, CDCl ₃ / CD ₃ OD) δ = 0.80 (t, 3H, J = 6.6), 1.05-1.28 (m, 24H), 1.37-1.57 (m, 2H), 1.69-1.81 (m, 3H), 2.05 (t, 2H, J = 7.5), 2.31 (s, 3H). 2.35 (s, 3H), 2.48-2.75 (m, 2H), 3.84-4.05 (m, 5H), 5.18 (s, 2H), 6.90 (d, 2H , J = 8.6), 7.05 (d, 2H, J = 8.6), 8.39 (s, 1H). 13 C NMR (300 MHz, CD 3 OD) δ = 10.19, 11.02, 13.96 , 14.23, 14.41, 23.71, 27.13, 30.25, 30.46, 30.62, 30.78, 33.05, 37.40, 41.15, 52.85, 61.81, 65.77, 67.48, 116.07, 131.61, 131.66, 133.75, 133.85, 157.70, 176.03.HRMS (ESI) m / z = 633.4033 (M ⁺ , C ₃₅ H ₅₈ N ₂ O ₆ P Required 633.4033).

  (1R)-(3-Hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -butyl) -phosphonic acid (vpc51303 )

¹ H NMR (300MHz, CD ₃ OD) δ = 0.89 (t, 3H, J = 6.7), 1.12-1.39 (m, 22H), 1.40-1.55 (m, 2H), 1.56-1.72 (m, 2H), 1.72-1.91 (m, 2H), 2.09 (t, 2H, J = 7.3), 2.58-2.83 (m, 2H), 3.93-4.12 (m, 3H), 4.90 (q, 2H, J = 8.1), 5.28 (s, 2H), 6.98 ( d, 2H, J = 8.1), 7.18 (d, 2H, J = 8.2), 7.42 (bs, 1H), 7.59 (bs, 1H), 8.61 (bs, 1H). 13 C NMR (300 MHz, CD ₃ OD) δ = 14.39, 23.71, 27.10, 28.89 (d, ¹ J _{C, P} = 28.21 Hz), 30.22, 30.44, 30.60, 30.76, 33.03, 37.25, 41.01, 62.19, 66.63 ( t, ² J _{C, F} = 36.3 Hz), 115.88, 122.66, 126.32, 131.56, 133.48, 146.01, 157.76, 158.10, 169.14, 170.74, 176.11.HRMS (ESI) m / z = 673.3597 (M ⁺ , C ₃₄ H ₅₃ F ₃ N ₂ O ₆ P Required value 673.3593).

  (1S)-(3-Hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -butyl) -phosphonic acid (vpc52162 )

  This product has spectral characteristics similar to its enantiomer.

  (1R)-(3-Tetradecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -butyl) -phosphonic acid (vpc52079 )

¹ H NMR (300MHz, CD ₃ OD) δ = 0.88 (t, 3H, J = 6.5), 1.09-1.35 (m, 20H), 1.44-1.57 (m, 2H), 1.60-1.90 (m, 2H), 2.00-2.18 (m, 2H), 2.62-2.82 (m, 2H), 3.95-4.12 (m, 3H), 4.99 (q, 2H, J = 8.0), 5.37 (s, 2H), 6.70 (d, 1H , J = 8.8), 7.01 (d, 2H,
J = 8.6), 7.20 (d, 1H, J = 8.7), 7.57 (bs, 1H), 7.72 (bs, 1H), 8.70 (bs, 1H) .HRMS (ESI) m / z = 645.3273 (M ⁺ , C ₃₂ H ₄₉ F ₃ N ₂ O ₆ P Required value 645.3280).

  (1S)-(3-Tetradecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -butyl) -phosphonic acid (vpc52163 )

  This product has spectral characteristics similar to its enantiomer.

  [4- [4- (tert-butyl-dimethyl-silanyloxy) -phenyl] -3- (9H-fluoren-9-ylmethoxycarbonylamino) -trans-but-1-enyl] -phosphonic acid diethyl ester, or [ 4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3- (tert-butoxycarbonylamino) -trans-but-1-enyl] -phosphonic acid diethyl ester

A solution of NaH (60% in mineral oil, 375 mg, 9.4 mmol) in THF (15 ml) cannulated with the appropriate tetra-ethyl diphosphonic acid (9.4 mmol) in THF (15 ml) at 0 ° C. Add by insertion. The mixture is stirred at 0 ° C. for 30 minutes and aldehyde dissolved in THF (25 ml) is added via cannulation. The mixture is left stirring for a further 30 minutes at 0 ° C. Excess NaH is quenched with saturated aqueous ammonium chloride and the aqueous layer is extracted with ethyl acetate. The organic layer is washed with brine, dried (MgSO ₄ ), evaporated to dryness and subjected to flash chromatography (1: 1 hexane: EtOAc to 100% EtOAc) to give the product as a pale yellow oil. To obtain (yield 43%).

  (3R)-[4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3- (tert-butoxycarbonylamino) -trans-1-chloro-but-1-enyl] -phosphonic acid diethyl ester

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.07 (s, 6H), 0.87 (s, 9H), 1.21 (q, 6H, J = 8.0, 7.5), 1.30 (s, 9H), 2.68-2.94 (m , 2H), 3.73-4.08 (m, 4H), 4.76 (bs, 1H), 4.76 (bs, 1H), 6.64 (d, 2H, J = 8.4), 6.74 (dd, 1H, J = 13.3, 9.9) , 6.97 (d, 2H, J = 8.4). 13 C NMR (300 MHz, CDCl 3) δ = -5.02, 15.63 (d, 3 J C, P = 8.0 Hz), 17.57, 25.10,
27.80, 38.67, 50.42 (d, ³ J _{C, P} = 16.1 Hz), 62.53 (dd, ² J _{C, P} = 13.0, 5.0 Hz), 76.36, 119.39, 121.94 (d, ¹ J _{C, P} = 207.51) , 128.73, 129.91, 164.10 (d , 2 J C, P = 16.1 Hz), 153.89, 154.54, 155.39, 169.49. 31 P NMR (121.5 MHz, CDCl 3) δ = 10.20. HRMS
(ESI), M ⁺ , Detected value: 548.2365. Calculated value for C ₂₅ H ₄₄ NO ₆ PSiCl, 548.2364.

  (3R)-[4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3- (9H-fluoren-9-ylmethoxycarbonylamino) -trans-1-fluoro-but-1-enyl] -Phosphonic acid diethyl ester

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.19 (s, 6H), 1.00 (s, 9H), 1.32 (t, 6H, J = 7.0),
2.70-3.03 (m, 2H), 3.89-4.22 (m, 4H), 4.29-4.45 (m, 2H), 4.83-5.00 (m, 1H), 5.51 (d, 1H, J = 6.8), 5.98 (dt , 1H, J = 38.5, 8.1), 6.78 (d, 2H, J = 8.4), 7.07 (d, 2H, J = 7.0), 7.28-7.43 (m, 4H), 7.59 (d, 2H, J = 7.5 ), 7.77 (d, 2H, J = 7.3).
¹³ C NMR (300 MHz, CDCl ₃ ) δ = -4.60, 16.04 (d, ³ J _{C, P} = 6.0 Hz), 18.00, 25.51, 39.93, 47.06, 63.16 (dd, ² J _{C, P} = 14.1, 6.0 Hz), 66.64, 119.84, 124.92, 125.50 (dd,
_{^{1 J C, P = 27.2,}} 5.1), 126.95, 127.56, 128.90, 130.23, 141.15, 143.77, 154.46, 155.34. 31 P NMR (121.5 MHz, CDCl 3) δ = 5.21 (d, J = 99.6 Hz). 19 F NMR (282 MHz, CDCl ₃ ) δ = -126.77 (dd, J = 101.1, 39.6 Hz) .HRMS (ESI), M ⁺ , detected value: 654.2089. Calculated value of C ₃₅ H ₄₆ FNO ₆ PSi, 654.2816.

  (3S)-[4- [4- (tert-Butyl-dimethyl-silanyloxy) -phenyl] -3- (9H-fluoren-9-ylmethoxycarbonylamino) -trans-1-fluoro-but-1-enyl] -Phosphonic acid diethyl ester

  This product has spectral characteristics similar to its enantiomer.

  (3R)-[4- (4-Hydroxy) -phenyl] -3- (tert-butoxycarbonylamino) -trans-1-chloro-but-1-enyl] -phosphonic acid diethyl ester

¹ H NMR (300MHz, CDCl ₃ ) δ = 1.15-1.34 (m, 6H), 1.38 (s, 9H), 2.65-2.96 (m, 2H), 3.81-4.18 (m, 4H), 4.83 (bs, 1H ), 5.05 (bs, 1H) , 6.68-6.79 (m, 3H), 6.98 (d, 2H, J = 8.4). 13 C NMR (75.5 MHz, CDCl 3) δ = 15.80 (d, 3 J C, P = 6.1 Hz), 27.99, 38.51, 50.45 (d, ³ J _{C, P} = 12.1 Hz), 63.25 (dd, ² J _{C, P} = 10.1, 5.0 Hz), 76.36, 115.25,
_{^{122.02 (d, 1 J C,}} P = 195.42), 126.52, 130.15, 146.51 (d, 2 J C, P = 18.1 Hz), 155.66, 172.16. 31 P NMR (121.5 MHz, CDCl 3) δ = 10.16. Δ = HRMS (ESI), M ⁺ , Detected value: 456.1313.Calculated value of C ₁₉ H ₂₉ NO ₆ PClNa, 456.1319.

  (3R)-[4- (4-Hydroxy) -phenyl] -3- (tert-butoxycarbonylamino) -trans-1-fluoro-but-1-enyl] -phosphonic acid diethyl ester

¹ H NMR (300MHz, CDCl ₃ ) δ = 1.21-1.35 (m, 6H), 1.41 (s, 9H), 2.63-2.90 (m, 2H), 3.85-4.15 (m, 4H), 4.81 (bs, 1H ), 5.83 (dt, 1H, J = 38.1, 7.0), 6.75 (d, 2H, J = 8.1), 6.99 (d, 2H, J = 7.3), 7.63 (bs, 1H). ¹³ C NMR (75.5 MHz , CDCl ₃ ) δ = 16.01 (d, ³ J _{C, P} = 6.0 Hz), 28.23, 39.79, 47.11, 63.49 (t, ² J _{C, P} = 6.0 Hz), 115.43, 125.98, 127.13, 130.39, 155.68, 171.74. ³¹ P NMR (121.5 MHz, CDCl ₃ ) δ = 5.61 (d, J = 102.7 Hz). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ = -127.41 (dd, J = 103.5, 39.1 Hz).

  (3R)-[1-Fluoro-3-hexadecanoylamino-4- (4-hydroxy-phenyl) -trans-but-1-enyl] -diethyl phosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.87 (t, 3H, J = 6.7), 1.20-1.35 (m, 30H), 1.50-1.63 (m, 2H), 2.12 (t, 2H, J = 7.5) , 2.69-2.95 (m, 2H), 3.84-4.18 (m, 4H), 5.11-5.26 (m, 1H), 5.89 (dt, 1H, J = 38.6, 8.1), 6.05 (d, 1H, J = 8.1 ), 6.75 (d, 2H, J =
8.4), 6.99 (d, 2H , J = 8.4). 13 C NMR (300 MHz, CDCl 3) δ = 14.07, 16.03 (dd, 3 J C, P = 8.1, 4.0 Hz), 22.62, 25.59, 29.19, 29.30, 29.46, 29.65, 31.86, 36.56, 39.85, 45.86 (d, ³ J _{C, P} = 12.1 Hz), 63.55 (dd, ² J _{C, P} = 10.1, 5.0 Hz), 115.46, 125.63 (d, ¹ J _{C, P = 28.21 Hz),} 127.03, 130.28, 155.98, 172.94. 31 P NMR (121.5 MHz, CDCl 3) δ = 5.25 (d, J = 101.1 Hz). 19 F NMR (282 MHz, CDCl 3) δ = -126.62 (dd, J =
(101.5, 38.2 Hz).

  (3S)-[1-Fluoro-3-hexadecanoylamino-4- (4-hydroxy-phenyl) -trans-but-1-enyl] -diethyl phosphonate

  This product has spectral characteristics similar to its enantiomer.

General procedure for Boc deprotection and acylation. Synthesis of diethyl {4- [4- (OR) -phenyl] -3-acylamino-trans-but-1-enyl} -phosphonate

Diethyl [4- [4- (OR) -phenyl] -3- (N-Boc) -trans-but-1-enyl] -phosphonate (1.3 g, 2.0 mmol) in CH ₂ Cl ₂ (10 ml) Add trifluoroacetic acid (3 ml) to the melt. The solution is stirred at room temperature under N ₂ for 2 hours and then evaporated to dryness to give the free amine. To the amine dissolved in CH ₂ Cl ₂ (50 ml), Hunig's base (6.0 mmol, 1.1
ml) and acid chloride (2.4 mmol) was added and the mixture stirred at room temperature, N ₂ below. Upon completion as determined by TLC, the solvent is evaporated under reduced pressure and the residue is subjected to flash chromatography to give the product as a yellow oil (yield 60-80%).

  (3R)-(3-tert-butoxycarbonylamino-1-chloro-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans- But-1-enyl) -phosphonic acid diethyl

¹ H NMR (300MHz, CDCl ₃ ) δ = 1.24-1.34 (m, 6H), 1.37 (s, 9H), 2.73-2.98 (m, 2H), 3.84-4.20 (m, 4H), 4.40 (q, 2H , J = 7.9), 4.81 (bs, 1H), 5.12 (s, 2H), 6.70-6.85 (m, 2H), 6.89 (d, 2H, J = 8.8), 7.08-7.12 (m, 3H), 8.45 (d, 1H, J = 5.7 ). 13 C NMR (75.5 MHz, CDCl 3) δ = 16.11 (d, 3 J C, P = 8.1 Hz), 28.20, 38.78, 52.03 (d, 3 J C, P = 21.2 Hz), 63.00-63.33 (m, ² J _{C, P} ; ² J _{C, F} ), 70.16, 107.18, 109.10, 113.96,
114.79, 118.68 (d, ¹ J _{C, P} = 205.5 Hz), 128.98, 130.52, 145.99 (d, ² J _{C, P} = 6.0 Hz), 150.77, 159.50, 159.74, 164.12, 172.54. ³¹ P NMR (121.5 MHz , CDCl ₃ ) δ = 10.02. ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ = -74.04 (t, J = 7.93 Hz, 3F). HRMS (ESI), M ⁺ , detected value: 623.1906. C ₂₇ H ₃₆ Calculated value for ClF ₃ N ₂ O ₇ P, 623.1901.

  (3R)-(1-Chloro-3-hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but -1-enyl) -diethylphosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.86 (t, 3H, J = 6.7), 1.19-1.36 (m, 30H), 1.47-1.59 (m, 2H), 2.10 (t, 2H, J = 7.5) , 2.80-2.97 (m, 2H), 3.88-4.17 (m, 4H), 4.41 (q, 2H, J = 7.9), 5.12 (apparent s, 3H), 5.93 (d, 1H, J = 7.69), 6.72-6.80 (m, 2H), 6.90 (d, 2H, J = 8.6), 7.12 (apparent d, 3H, J = 8.8), 8.46 (d, 1H, J = 5.7). ¹³ C NMR (300 MHz , CDCl ₃ ) δ = 14.05, 16.11 (d, ³ J _{C, P} = 8.1 Hz), 20.97, 22.62, 25.51, 28.87, 29.19, 29.30, 29.43, 29.59, 31.86, 36.51, 38.57, 49.45 (d, ³ J _{C, P} = 16.1 Hz), 63.78 (q, ² J _{C, P} = 6.0 Hz), 64.85 (q, ² J _{C, F} = 36.26), 70.11, 107.23, 109.08, 114.79, 120.84 (d, ¹ J _{C , P} = 187.4 Hz), 129.00, 130.47, 145.74 (d, ² J _{C, P} = 18.1
Hz), 150.77, 157.13, 159.66 , 164.12, 172.51. 31 P NMR (121.5 MHz, CDCl 3) δ = 9.80. 19 F NMR (282 MHz, CDCl 3) δ = -74.04 (t, J = 7.93 Hz, 3F ).

  (3R)-(3-tert-Butoxycarbonylamino-1-fluoro-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans- But-1-enyl) -phosphonic acid diethyl

¹ H NMR (300MHz, CDCl ₃ ) δ = 1.24 (t, 3H, J = 7.0), 1.30 (t, 3H, J = 7.0), 1.87
(s, 9H), 2.65-2.97 (m, 2H), 3.84-4.14 (m, 4H), 4.38 (q, 2H, J = 7.9), 4.79 (bs,
1H), 5.10 (s, 2H), 5.84 (dt, 1H, J = 38.6, 7.0), 6.77 (dt, 1H, J = 5.7, 2.4), 6.88 (d, 2H, J = 8.8), 7.09 (apparent) D, 3H, J = 8.6), 8.43 (d, 1H, J = 5.7). ¹³ C
NMR (75.5 MHz, CDCl ₃ ) δ = 16.04 (d, ³ J _{C, P} = 6.1 Hz), 28.18, 38.79, 47.25, 63.10
(dd, ² J _{C, P} , J = 12.1, 6.1) 64.78 (q, ² J _{C, F} , J = 36.26), 70.11, 107.15, 109.05, 114.69, 125.75 (d, ¹ J _{C, P} = 32.2 Hz), 129.19, 130.44, 150.74, 154.78, 157.02, 159.69, 164.04, 171.76. ³¹ P NMR (121.5 MHz, _{CDCl 3) δ = 5.59 (d} , J = 99.5). 19 F NMR (282 MHz, CDCl 3) δ = -127.22 (dd, J = 105.65, 40.14, 1F), -74.05 (t, J = 7.93
Hz, 3F).

  (3R)-(1-Fluoro-3-hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but -1-enyl) -diethylphosphonate

¹ H NMR (300MHz, CDCl ₃ ) δ = 0.85 (t, 3H, J = 6.5), 1.16-1.33 (m, 30H), 1.48-1.60 (m, 2H), 2.09 (t, 2H, J = 7.6) , 2.70-2.99 (m, 2H), 3.85-4.15 (m, 4H), 4.40 (q, 2H, J = 7.9), 5.10 (apparent s, 3H), 5.87 (dt, 1H, J = 38.7, 8.3 ), 6.19 (d, 1H, J = 8.14), 6.78 (dd, 1H, J = 5.60, 2.6), 6.88 (d, 2H, J = 8.8), 7.10 (apparent d, 3H, J = 8.6), 8.43 (d, 1H, J = 5.7). 13 C NMR (300 MHz, CDCl 3) δ = 14.02, 16.04 (d, 3 J C, P = 6.1 Hz), 22.59, 25.53, 29.16, 26.24, 29.30, 29.41 , 29.59, 31.81, 36.54, 39.71, 45.45 (dd, ³ J _{C, P} = 12.1, 4.0 Hz), 63.25 (dd, ² J _{C, P} = 16.1, 4.0 Hz), 65.03 (t, ² J _{C, F} = 36.3), 70.08, 107.18, 109.02, 114.66, 125.40 (dd, ¹ J _{C, P} = 28.2, 4.0 Hz), 129.30, 130.42, 150.74, 157.02, 159.66, 164.07, 172.08, 172.43. ³¹ P NMR
_{(121.5 MHz, CDCl 3) δ} = 5.11 (d, J = 99.5). 19 F NMR (282 MHz, CDCl 3) δ = -126.55 (dd, 1F, J = 38.64, 100.08), -74.06 (t, 3F , J = 7.93 Hz). HRMS (ESI), M ⁺ , Detected value: 745.3945. Calculated value of C ₃₈ H ₅₈ F ₄ N ₂ O ₆ P, 745.3969.

  (3S)-(1-Fluoro-3-hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but -1-enyl) -diethylphosphonate

  This product has spectral characteristics similar to its enantiomer.

  (3R)-(1-Chloro-3-hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but -1-enyl) -phosphonic acid (vpc53048)

¹ H NMR (300MHz, CD ₃ OD: TFA) δ = 0.67 (t, 3H, J = 6.3), 1.05 (apparent s, 24H), 1.24-1.36 (m, 2H), 1.90 (q, 2H, J = 7.0), 2.58-2.73 (m, 2H), 4.83 (q, 2H, J = 7.9), 5.20 (s, 2H), 6.40-6.49 (m, 1H), 6.82 (d, 2H, J = 8.4) , 7.02 (d, 2H, J = 8.4), 7.42 (dd, 1H, J = 6.9, 2.8), 7.55 (d, 1H, J = 2.2), 8.51 (d, 1H, J = 6.8). ¹³ C NMR (75.5 MHz, CD ₃ OD: TFA) δ = 14.44, 23.76, 26.97, 30.25, 30.46, 30.62, 30.81, 33.08, 37.11, 39.76, 66.68, 67.55 (d, ² J _{C, F} = 38.3), 112.67, 113.85 , 116.01, 124.83 (d, ¹ J _{C, P} = 189.37 Hz), 131.93, 132.62, 141.95 (d, ² J _{C, P} = 20.1 Hz), 159.73, 160.27, 170.12, 175.60. ³¹ P NMR (121.5 MHz, CD ₃ OD: TFA) δ = 6.71. ¹⁹ F NMR (282 MHz, CD ₃ OD: TFA) δ = -75.73 (t, J = 7.93 Hz, 3F). HRMS (ESI), M ⁺ , detected value: 705.3086 Calculated value for C ₃₄ H ₅₀ ClF ₃ N ₂ O ₆ P, 705.3047.

  (3R)-(1-Fluoro-3-hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but -1-enyl) -phosphonic acid (vpc52298)

¹ H NMR (300MHz, CD ₃ OD: TFA) δ = 0.61 (t, 3H, J = 6.5), 0.99 (apparent s, 24H), 1.17-1.29 (m, 2H), 1.82 (t, 2H, J = 7.3), 2.38-2.66 (m, 2H), 5.14 (s, 2H), 5.47 (dt, 1H, J = 38.9, 7.9), 6.76 (d, 2H, J = 8.1), 6.95 (d, 2H, . J = 8.1), 7.35 ( dd, 1H, J = 5.7), 7.49 (s, 1H), 8.44 (d, 1H, J = 6.2) 13 C NMR (75.5 MHz, CD 3 OD: TFA) δ = 14.44 , 23.76, 26.97, 30.25, 30.46, 30.62, 30.78, 33.08, 37.11, 40.88, 66.
71, 67.54 (d, ² J _{C, F} = 38.3), 112.65, 113.85, 115.96, 124.95 (d, ¹ J _{C, P} = 38.3 Hz),
131.88, 132.84, 144.80, 157.49, 160.29, 169.59, 175.44. ³¹ P NMR (121.5 MHz, CD ₃ OD: TFA) δ = 2.35 (d, 1P, J = 109.2). ¹⁹ F NMR (282 MHz, CD ₃ OD : TFA) δ = -127.54 (dd, 1F, J = 108.48, 39.14), -75.73 (t, 3F, J = 7.93 Hz) .HRMS (ESI), M ⁺ , detected value: 689.3335. C ₃₄ H ₅₀ F ₄ Calculated N ₂ O ₆ P, 689.3343.

  (3S)-(1-Fluoro-3-hexadecanoylamino-4- {4- [4- (2,2,2-trifluoro-ethoxy) -pyridin-2-ylmethoxy] -phenyl} -trans-but -1-enyl) -phosphonic acid (vpc52300)

  This product has spectral characteristics similar to its enantiomer.

  Epidermoid cancer

Human epidermoid carcinoma A431 cells mobilize calcium by a combination of LPA ₁ and LPA ₃ receptors, loaded with calcium sensitive fluorescent dye, and 1-oleoyl LPA in the presence of the indicated concentration of VPC51299. Was used to investigate closely. The results are illustrated in FIG.

  LPA suppression

  Rat glioma C62B cells accumulate cAMP in response to isoproterenol, and this adenylyl cyclase stimulation is blocked by LPA. As shown, LPA suppression of adenylyl cyclase activation is mitigated by adding any of VPC51299, VPC52172, VPC52173, and VPC52178 in a dose-dependent manner. The results are illustrated in FIG.

  Melanoma cell migration

Human melanoma A2058 cells (1 × 10 ⁵ ) were placed on top of the modified Boydon chamber. The indicated compound was placed in the lower chamber, and after 4 hours at 37 ° C., the cells were collected from the lower side of the thin film (8 μm pore size, with Matrigel® coating) and the mass was determined. The results are illustrated in FIG.

On day 0, mice were injected subcutaneously with 400,000 B16F1 melanoma cells, and from day 7 the test compound VPC51299 / vehicle was injected intraperitoneally 25 mg / kg once a day. 5 C57BL / 6 (female, 8-9 weeks). By convention, mice are euthanized when tumor size exceeds 225 mm ³ (tumor volume = (L × W × W) / 2: day 11 for vehicle treatment). The tumor was first palpated on day 8. The results are illustrated in FIGS. 5 and 6A-6B.

  CAM test method: (chorion membrane):

  On the third day of embryo development, the chick fertilized eggs were opened to expose the chorioallantoic membrane. After an additional 4 days of incubation, a 5 mm diameter filter paper plug (Whatman GF / C) is applied to the membrane and applied to the medium (bovine serum albumin (FAF_BSA) without 3% fatty acids) or to the medium at the indicated concentration. Soaked 20 microliters of any dissolved compound. Application of the solution was repeated daily for 3 days (embryonic age 7-9). On the 10th day of embryonic age, the filter paper plug was removed, the thin film under it was excised, fixed in formalin, and examined with a light microscope. Quantification was achieved by counting the number of small diameter vessels that run perpendicular to the disk image. The results are illustrated in FIGS. 7 and 8A-8D.

  Neuropathic pain

  To assess the efficacy of the test compound VPC51299 in reducing thermal hyperalgesia and mechanical allodynia, the neuropathic pain strangulation nerve injury (CCI) model (Bennett and Xie, Pain, 33 p87-107 (1988) )It was used. Adult male SD rats were anesthetized and the sciatic nerve was exposed at the center of the thigh. The wounds were closed by loosely ligating four chrome gut sutures around the sciatic nerve. In sham surgery, the sciatic nerve was mobilized and the wound closed without ligation. Animal response to mechanical and thermal stimuli was assessed before CCI and 1, 3, 5, 7 and 14 days after CCI.

  Thermal hyperalgesia was measured using a Plantar Test device (IITC Inc, Woodland Hills, CA). Rats were placed on a warmed glass surface, allowed to acclimatize, and a thermal stimulus was applied to the sole of the hind paw. Paw response time (PWL) is defined as the time from when a stimulus is applied until the foot is pulled. The results are illustrated in FIG. 9A.

  Mechanical allodynia was measured in two ways. First, a Von Frey monofilament of size 5.18 (equivalent to 15.0 g) was applied to the sole of the hind foot (Touch Test Sensory Evaluator Kit, Stoelting Co., Wooddale, Ill.). The number of pulls during 10 3-second trials was recorded. The results are illustrated in FIG. 9B. Second, the maximum threshold of subtraction reaction was evaluated using an electronic Von Frey Anesthesiometer (IITC Inc, Woodland Hills, CA). Force was applied to the plantar surface of the hind paw until the rat pulled the paw. The maximum force applied to the foot until the pulling action occurred was recorded. The results are illustrated in FIG. 9C.

  In these experiments, VPC51299 was shown to be effective in alleviating thermal hyperalgesia and mechanical allodynia associated with CCI. On the fifth day, after 5 days of treatment, rats receiving VPC51299 had a paw movement 3.1 seconds slower than the vehicle-treated rat, and the number of raising the paw was 3.2 times faster than the vehicle-treated rat. Less often (out of 10 trials) and the pulling threshold was 4.0 g higher than the vehicle-treated rats.

  HM7 tumor growth

Forty-five mice were inoculated with 5 million HM7 cells in PBS (phosphate buffered saline) subcutaneously (SQ) in the lower right side of the dorsal side in a volume of 0.2 ml per mouse. When the tumor reaches 200 mm3,
Animals were not included in 3 groups of 10 animals containing vehicle (2% hydroxypropyl beta cyclodextrin) oral dose 0.5 ml, FTY720 (10 mg / kg) oral dose 0.5 ml, and compound 51299 (15 mg / kg) subcutaneous dose 0.1 ml. Divided into work.

  Micro CT angiography

The animals received an intraperitoneal injection of 0.05 ml of heparin 10 minutes before being euthanized by inhalation of carbon dioxide. The chest cavity was opened, an incision was made in the apex of the heart, a polyethylene cannula (inner diameter 0.58 mm, outer diameter 0.97 mm) was passed through the left ventricle and fixed with 5-0 silk suture in the ascending aorta. 17 ml of a 0.1 mM sodium nitroprusside solution in 0.9% saline was perfused at a rate of 6 ml / min to provide maximum vasodilation and remove blood. As recommended by the manufacturer, a commercially available chromate latex MICROFIL ^™ (Carver, Mass.) Was prepared and 17 ml perfused at a rate of 2 ml per minute. The infused latex mixture was allowed to polymerize at room temperature for 60 minutes before incising the target tissue. The dissected tumor was immersed in 10% neutral buffered formalin.

  The tumors were then imaged with a μCT40 (SCANCO Medical, Basseldorf, Switzerland) X-ray micro computed tomography (micro CT) system. Tumors were imaged using soybean oil as the background medium. Micro CT images were created by operating the X-ray tube at an energy level of 45 kV, a current of 177 μA, and an integration time of 450 ms. Axial images were acquired with an isotropic resolution of 16 μm.

  Vascular networks and tumors were extracted by a series of image processing procedures. Intensity threshold 1195 Hounsfield units (HU) and morphological filtering (erosion and dilation) were applied to volumetric micro-CT image data to extract vessel volume (VV). Tumor volume (TV) was extracted from the background in a similar manner using an intensity threshold of -8 HU. Vessel density (VV / TV) was determined from the ratio of VV to TV. Vessel and tumor intensity thresholds were determined by visual inspection of the results of subdivision from a subset of samples. Estimated blood vessel size is a thinning algorithm that employs boundary distance transformation and single point distance transformation techniques (Zhou, Y. et al., IEEE Trans. Visualization and Computer Graphics, 1999; 5 [3]: 196-209). As a basis. The calculations were performed with an in-house image analysis algorithm written in C ++ and Python using the AVW image processing software library (AnalyzeDirect Inc., Lenexa, Kansas). Three-dimensional (3D) surface rendering was created from the micro-CT data using Analyze 6.0 (AnalyzeDirect Inc., Lenexa, Kans.), An image analysis software package.

  Statistical analysis was performed using the JMP statistical software package (SAS Institute Inc., Curry, NC, USA). Comparison of groups of micro CT metrics (VV, TV, VV / TV) was evaluated using Dunnett's test for multiple comparisons. P values less than 0.05 were considered significant. The results are illustrated in FIG. 10 for the control (vehicle), FIG. 11 for the control FTY-720 and FIG. 12 for the test compound 51299.

  Bone metastases

Mice were tested for assessment of lytic bone metastasis. Athymic (nude) mice were injected with osteotropic subclone of human breast cancer cell line MDA MB-231. Two weeks later, the bones were scanned for cancer in the bones. The cancer was treated for 2 weeks and the lesion was imaged. In mice treated with LPA ₁ receptor antagonists such as VPC51299 or Boucharaba, A., et al. (2006) Proc. Natl. Acad. Sci v. 103, pp. 9643-9648 . The results are illustrated in FIG.

The disclosures of each patent, patent application, and publication cited herein are hereby expressly incorporated into this disclosure by reference in their entirety. The illustrative examples of the present disclosure have been considered and reference has been made to possible variations within the scope of the present disclosure. These and other variations and modifications in this disclosure will become apparent to those skilled in the art without departing from the scope of this disclosure, and it is to be understood that this disclosure and the following claims are described herein. It is not limited to the illustrative example.

Claims (33)

A compound having the following formula:

In this formula, Z is -CY = CH- or -C≡C-, where when Z is -CY = CH-, the double bond has a trans (e) structure,
Y is hydrogen or halogen,
Each R ¹ is independently halo, (C ₁ -C ₆ ) alkyl, halo (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -NH ₂ , -NH (C ₁ -C ₆ ) Alkyl, --N ((C ₁ -C ₆ ) alkyl) ₂ , or cyano, and
R ² is hydrogen, halo, (C ₁ -C ₁₂ ) alkyl, halo (C ₁ -C ₁₂ ) alkyl, halo (C ₁ -C ₁₂ ) alkoxyl, (C ₃ -C ₁₀ ) cycloalkyl, (C ₂ -C ₁₂ ) alkenyl, (C ₂ -C ₁₂ ) alkynyl, -NH ₂ , -NH (C ₁ -C ₁₂ ) alkyl, -N ((C ₁ -C ₁₂ ) alkyl) ₂ , aryl, (C _1- C ₁₂ ) alkaryl, aryl (C ₁ -C ₁₂ ) alkyl, or aryl-substituted aryl (C ₁ -C ₁₂ ) alkyl,
Each R ³ is independently halo, (C ₁ -C ₁₂ ) alkyl, halo (C ₁ -C ₁₂ ) alkyl, halo (C ₁ -C ₁₂ ) alkoxyl, (C ₃ -C ₁₀ ) cycloalkyl, ( C ₂ -C ₁₂₎ alkenyl, (C ₂ -C _{12) alkynyl, -NH 2, -NH (C 1} -C 12) _{alkyl, -N ((C 1 -C 12} ) alkyl) _2, aryl, (C ₁ -C ₁₂ ) alkaryl, aryl (C ₁ -C ₁₂ ) alkyl, or aryl-substituted aryl (C ₁ -C ₁₂ ) alkyl,
R ⁴ is (C ₆ -C ₂₄ ) alkyl, halo (C ₆ -C ₂₄ ) alkyl, (C ₆ -C ₂₄ ) alkoxy, -NH ₂ , -NH (C ₁ -C ₂₄ ) alkyl, -N ( (C ₁ -C ₂₄ ) alkyl) ₂ , cyano, (C ₃ -C ₁₀ ) -cycloalkyl, (C ₄ -C ₁₅ ) -bicycloalkyl, (C ₆ -C ₂₄ ) alkenyl, (C ₆ -C ₂₄ ) Alkenyl, (C ₆ -C ₂₄ ) -alkynyl, aryl, (C ₆ -C ₂₄ ) alkaryl, aryl (C ₆ -C ₂₄ ) alkyl, or aryl-substituted aryl (C ₆ -C ₂₄ ) alkyl,
Here, the alkyl group, alkenyl group and aryl group of R4 can be optionally substituted with halo, alkoxy or cyano,
R ⁵ and R ⁶ are independently hydroxy, (C ₁ -C ₁₂ ) alkyl-O-, (C ₂ -C ₁₂ ) alkenyl-O-, (C ₂ -C ₁₂ ) alkynyl-O-, (C ₆ -C ₁₀ ) aryl-O-,

m is 0, 1, 2, 3, or 4 and n is 0, 1, 2, or 3, or a pharmaceutically acceptable salt or ester thereof. R ² is hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, 1,1,1-trifluoroethoxy, methoxy, ethoxy, propoxy, butoxy, 2. The compound of claim 1 which is pentoxy.   The compound of claim 1 or 2, wherein Z is -CY = CH-.   The compound according to claim 1 or 2, wherein Z is -C≡C-.   The compound of any one of claims 1 to 4, wherein Y is hydrogen, fluorine, chlorine or bromine.   6. The compound of claim 5, wherein Y is hydrogen or fluorine.   7. The compound of claim 6, wherein Y is fluorine. R ¹ is fluorine, chlorine, bromine, trifluoro-methyl, methoxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, or (C ₁ -C ₆ ) alkyl substituted with alkoxy or cyano 8. Any compound of claims 1-7. 9. The compound of claim 8, wherein R ¹ is fluorine, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, 1,1,1-trifluoroethoxy, methoxy, or ethoxy. R ³ is fluorine, chlorine, bromine, trifluoro-methyl, methoxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, or (C ₁ -C ₆ ) alkyl substituted with alkoxy or cyano Any compound of claims 1-9. 11. The compound of claim 10, wherein R ³ is fluorine, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, 1,1,1-trifluoroethoxy, methoxy, or ethoxy. R ² is hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, 1,1,1-trifluoroethoxy, methoxy, ethoxy, propoxy, butoxy, Or any compound of claims 1 to 11 which is pentoxy. 13. The compound of claim 12, wherein R ² is hydrogen, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, or 1,1,1-trifluoroethoxy. R ² is hydrogen, compound of claim 13 trifluoromethoxy or 1,1,1-trifluoroethoxy,. The compound of any one of claims 1 to 14, wherein R ⁴ is alkyl or alkenyl. R ⁴ _{is, C 5 H 11, C 6} H 13, C 7 H 14 CH = CHC 8 H 17 or a compound of claim 15 which is a C ₁₅ H _31. R ⁴ is, compounds of _{C 7 H 14 CH = CHC 8} H 17 and C ₁₅ H ₃₁ in which claim 16. R ⁵ and R ⁶ are independently trifluoromethoxy, 1,1,1-trifluoroethoxy, methoxy, ethoxy,
18. Any compound of claims 1-17. R ⁵ and R ⁶ are independently hydroxy, methoxy, or ethoxy,
19. The compound of claim 18, wherein R ⁵ and R ⁶ are, independently hydroxy, methoxy compound of claim 19 or ethoxy.   21. Any compound of claims 1-20 having an ester functionality. The compound of claim 1 having the formula:
  23. A composition comprising any compound of claims 1-22 and a pharmaceutically acceptable carrier.   23. A method for the prevention or treatment of a pathological condition or symptom in a mammal, wherein an antagonist of LPA receptor is involved, the antagonism of which is desirable, and an effective amount of any compound of claims 1 to 22 is said mammal A method comprising administering to an animal.   A method for inhibiting angiogenesis in a tumor, comprising contacting an effective amount of a tumor cell and any compound of claims 1 to 22 with a patient in need thereof.   25. A method for preventing, inhibiting or treating neuropathic pain comprising administering to a patient in need thereof an effective amount of any compound of claims 1-22.   A method for repairing vascular injury after catheterization, comprising contacting an effective amount of any compound of claims 1 to 22 in a diseased blood vessel lumen with a patient in need thereof Method.   23. A method comprising administering to a patient in need thereof an effective amount of any compound of claims 1 to 22 in a manner that reduces damage caused by ischemia reperfusion injury.   23. Any compound of claims 1-22 for use in drug therapy.   Use of any compound of claims 1 to 22 for the preparation of a medicament for the treatment of neoplastic diseases, neuropathic pain or ischemia reperfusion injury.   32. The use of claim 30, wherein the medicament is comprised of a liquid carrier.   32. Use according to any of claims 30 or 31, wherein the medicament is adapted for parenteral, aerosol or transdermal administration.   23. A pharmaceutical composition comprising at least one compound, an applicator, and instructions for its use in a kit for administering at least one compound of claims 1-22 to a patient in need thereof A kit consisting of